Clinical Practice Guidelines: Management of ... - Semantic Scholar

s4

Méndez-Sánchez N, et al.

, 2014; 13 (Supl. 1): s4-s40 May, Vol. 13 Supl. 1, 2014: s4-s40

Latin American Association for the Study of the Liver (LAASL) Clinical Practice Guidelines: Management of Hepatocellular Carcinoma On behalf of LAASL

Nahum Méndez-Sánchez,1 Ezequiel Ridruejo,2,3 Angelo Alves de Mattos,4 Norberto C. Chávez-Tapia,5 Rodrigo Zapata,6 Raymundo Paraná,7 Ricardo Mastai,8 Edna Strauss,9 Luis Gonzalo Guevara -Casallas, 10 Jorge Daruich,11 Adrian Gadano,12 Edison Roberto Parise,13 Misael Uribe,5 Nancy E. Aguilar-Olivos,5 Lucy Dagher,14 Ben-Hur Ferraz-Neto,15 Martha Valdés-Sánchez,16 Juan F. Sánchez-Avila17 1

Liver Research Unit. Medica Sur Clinic & Foundation. Mexico City, Mexico. Hepatology Section, Department of Medicine. Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno “CEMIC”. Ciudad Autónoma de Buenos Aires, Argentina. 3 Hepatology and Liver Transplant Unit. Hospital Universitario Austral, Pilar, Argentina. 4 Federal University of Health Sciences Porto Alegre, Brazil. 5 Digestive Diseases and Obesity Clinic, Medica Sur Clinic Foundation. México City, Mexico. 6 Hepatology and Liver Transplantation Unit. University of Chile School of Medicine, German Clinic. Santiago, Chile. 7 Associate Professor of School of Medicine - Federal University of Bahia Head of the Gastro-Hepatologist Unit of the University Bahia University Hospital. 8 Transplantation Unit. German Hospital.Buenos Aires, Argentina. 9 Clinical hepatologist of Hospital do Coraçao - São Paulo – Brazil. Professor of the Post Graduate Course in the Department of Pathology at the School of Medicine, University of São Paulo. 10 Department of Gastroenterology and Hepatology. San Vicente Foundation, University Hospital. Medellin, Colombia. 11 Hepatology Department, Clinical Hospital San Martín. University of Buenos Aires Buenos Aires, Argentina. 12 Section of Hepatology, Italian Hospital of Buenos Aires. Buenos Aires, Argentina. 13 Professor Associado da Disciplina de Gastroenterologia da Universidade Federal de São Paulo, Presidente Eleito da Sociedade Brasileira de Hepatologia. 14 Consultant Hepatologist. Metropolitan Policlinic- Caracas- Venezuela. 15 Director of Liver Institute – Beneficencia Portuguesa de São Paulo. Chief of Liver Transplantation Team. 16 Department of Pediatric Oncology National Medical Center “Siglo XXI”. Mexico City, Mexico. 17 Hepatology and Liver Transplantation Department National Institute of Nutrition and Medical Sciences “Salvador Zubirán” Mexico City, Mexico. 2

Correspondence and reprint request: Prof. Nahum Méndez-Sánchez, MD.,MSc,PhD., Liver Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Col. Toriello Guerra, Mexico City, Mexico. E-mail: [email protected] Telephone: +525-554247200 (4215); Fax: +525-55666-4031 Manuscript received: January 30, 2014. Manuscript accepted: April 30, 2014.

Clinical Practice Guidelines: Management of Hepatocellular Carcinoma of the ALEH.

, 2014; 13 (Supl. 1): s4-s40

s5

Clinical Practice Guidelines: Management of Hepatocellular Carcinoma ABSTRACT Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer death, and accounts for 5.6% of all cancers. Nearly 82% of the approximately 550,000 liver cancer deaths each year occur in Asia. In some regions, cancer-related death from HCC is second only to lung cancer. The incidence and mortality of HCC are increasing in America countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Clinical care and survival for patients with HCC has advanced considerably during the last two decades, thanks to improvements in patient stratification, an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and the introduction of novel therapies and strategies in prevention. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. These LAASL recommendations on treatment of hepatocellular carcinoma are intended to assist physicians and other healthcare providers, as well as patients and other interested individuals, in the clinical decision-making process by describing the optimal management of patients with liver cancer. Key words. Liver cancer. Treatment. Epidemiology. Consensus.

INTRODUCTION Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer death, and accounts for 5.6% of all cancers. Nearly 82% of the approximately 550,000 liver cancer deaths each year occur in Asia. In some regions, cancer-related death from HCC is second only to lung cancer. In Latin America it has been suggested that this neoplasia has increased. However, there is little information. Nevertheless, according to the prevalence of hepatitis C virus infection (and hepatitis B virus infection in some areas), obesity and alcohol intake in our region is expected that these speculations regarding its increase are true.

METHODOLOGY A steering committee was invited among the members of the Latin American Association for the Study of the Liver (LAASL) to proposed the content of the Hepatocellular Cancer Consensus based on previous international consensuses as well as in topics of regional interest. A list of members from all participant countries in the LAASL was selected by the steering committee based on expertise and trajectory. The list of chapters for the Consensus was then matched to each expert so that one member would be responsible for drafting an initial version. Each author received an instruction manual prepared by the steering committee with specific instructions and a precise objective for each chapter. Authors were instructed to prepare all manuscripts following a concise and clear logical argument based on the best available evidence. Chapters were exhaustive to avoid duplicity of content. Recommendations had to be weighted according to another classification of other scientific societies of scientific evidence (Table 1). Once all initial drafts were written the steering committee selected another member of the ALEH to provide blinded comments. Reviewers were instructed to analyze each chapter carefully evaluating the relevance, completeness, and present importance of the content and references. Reviewers were specifically asked to analyze the recommendations and confirm the assessment of the strength of the evidence. An external scientific group double checked all references and provided editorial services including the translation of the chapters to Spanish or English. Final chapters of the consensus were made available to all members of LAASL for external evaluation and comments.

s6


, 2014; 13 (Supl. 1): s4-s40

Table 1. Strength of evidence classification. Class of evidence • •

•

Class 1. Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective. Class 2. Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure, or treatment. ° Class 2a. Weight of evidence/opinion is in favor of usefulness/efficacy. ° Class 2b. Usefulness/efficacy is less well established by evidence/opinion. Class 3. Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure, or treatment is not useful/effective and in some cases may be harmful.

Level of Evidence • • •

Level A. Data derived from multiple randomized clinical trials or meta-analyses. Level B. Data derived from a single randomized trial or nonrandomized studies. Level C. Only consensus opinion of experts, case studies, or standard of care.


EPIDEMIOLOGY HCC prevalence varies by geographic region. The incidence is highest (20 per 100,000 individuals) in areas with endemic hepatitis B virus (HBV) infection, such as sub-Saharan Africa and Eastern Asia.1 Mediterranean countries such as Italy, Spain, and Greece have intermediate incidence rates (10 to 20 per 100,000 individuals), whereas North and South America have a relatively low incidence (< 5 per 100,000 individuals). The age distribution of HCC largely depends on the dominant type of viral hepatitis and the age at which it was acquired. In regions with a high HBV incidence, infection occurs at birth and HCC diagnosis is established 10 years earlier than in regions where HBV is less prevalent, such as North America or Europe, where the most common etiology is hepatitis C virus (HCV) acquired later in life. HCC is more common in men than in women probably because infection by HBV or HCV and alcohol consumption are more prevalent and possibly more carcinogenic in men. In 80 to 90% of cases, HCC occurs with cirrhosis.2 HCC in Latin America

s7

, 2014; 13 (Supl. 1): s4-s40

Table 2. Etiology of CLD in 240 patients with a diagnosis of HCC. Etiology

n

Percentage

HCV Alcohol Cryptogenic cirrhosis HBV HCV + alcohol Other NASH HBV + alcohol AIH HH HCV + HBV PBC HCV + HBV + alcohol

74 49 35 26 14 14 11 4 4 4 2 2 1

30.8 20.4 14.6 10.8 5.8 5.8 4.6 1.7 1.7 1.7 0.8 0.8 0.4

HCC: hepatocellular carcinoma. HCV: hepatitis C virus. HBV: hepatitis B virus. NASH: nonalcoholic steatohepatitis. AIH: autoimmune hepatitis. PBC: primary biliary cirrhosis. Information from reference 4.

found in 9% of the patients. Further studies are required to identify accurately the incidence, prevalence, mortality rate, and risk factors in Latin America. Etiology and risk factors

Information about the prevalence and incidence of, and risk factors for, HCC in Latin America is scarce. There are no reliable sources for the prevalence and incidence of HCC, but an approximation can be obtained from the cause-specific mortality rate, which was 4.1 per 100,000 in Mexico in 2000 and increased to 4.7 per 100,000 in 2006.3 A recent prospective study analyzed epidemiological aspects of HCC in Latin American countries.4 A total of 240 patients with HCC from nine countries were included in this study; the median age was 64 years, 72.5% of them were men, and 85.4% had underlying cirrhosis. The etiology of chronic liver disease (CLD) was HCV in 30.8% of patients, alcohol in 20.4%, cryptogenic cirrhosis in 14.6%, HBV in 10.8%, and HCV plus alcohol in 5.8% (Table 2). These results contrast with a retrospective study performed in Argentina,5 in which the main etiologies were chronic alcoholism in 41.6%, HCV in 40.5%, HBV in 13.4%, and cryptogenic cirrhosis in 9.2% of patients. In another recent study from Brazil,6 215 patients with diagnosis of HCC had a mean age of 57.3 (± 14.1) years, and 76.2% were men. The etiology of CLD was HCV and HBV infection in 43% and 23% of patients, respectively. Alcohol abuse alone or combined with other etiologies was identified in 32% of the patients. Schistosomiasis was

HCC etiology varies depending on the geographic location. In countries where HCC is endemic (subSaharan Africa, Asia, and Alaska), the most common cause is HBV infection, but in low-risk countries the most common HCC cause is cirrhosis, secondary to chronic viral infection or alcohol consumption.7 Cirrhosis Regardless of its cause, cirrhosis is a major clinical and histopathological risk factor for HCC. Onethird of cirrhotic patients will develop HCC during their lifetime.8 Long-term follow-up studies have reported that 1-8% of patients with cirrhosis develop HCC per year (e.g., 2% in HBV-infected cirrhotic patients and 3-8% in HCV-infected cirrhotic patients). In a Latin American study, 85% of HCC patients had underlying cirrhosis, whereas in a study from Argentina, cirrhosis was present in 93% of patients.4 The causes of cirrhosis include chronic viral hepatitis, alcohol abuse, inherited metabolic diseases such as hemochromatosis or alpha-1-antitrypsin deficiency, and nonalcoholic fatty liver disease (NAFLD). In a Mexican study of 1486 patients, the main

s8


risk factors for cirrhosis were alcohol consumption (39.5%), HCV (36.6%), cryptogenic (10.4%), primary biliary cirrhosis (5.7%), and HBV (5.0%).8 Hepatitis B Chronic HBV infection is a well-established HCC risk factor. In the USA, up to 25% of HCC patients are HBV positive.9 Other HBV-related factors are high viral load10 and genotype C,11 which are independent predictors of HCC development. Sex is an important factor in these patients because there is an association between high testosterone level and tumor development in early stages of HCC.7 Hepatitis C

, 2014; 13 (Supl. 1): s4-s40

causes alterations in hepatocyte DNA.7 Aflatoxin is an important cofactor for HCC development in some parts of Africa and Asia. There is a strong correlation between the dietary intake of aflatoxin B1, TP53 mutations, and the incidence of HCC, specifically in HBV-infected individuals.12 Hereditary hemochromatosis (HH) HH is a significant risk factor for HCC development. Its presence is associated with a 200-fold increased risk for HCC. 12 Iron toxicity in the liver is produced by free radical formation and lipid peroxidation within cells, and may eventually cause hepatocyte death, fibrosis, and cirrhosis.6 Wilson’s disease

HCV infection is recognized as a significant risk factor for HCC development, with 6-75% of HCC patients exhibiting antibodies to HCV.12,13 Some studies have identified genotype 1b as conferring a high risk for HCC development.14 A number of studies have demonstrated a direct relationship between HCC incidence and advanced stages of hepatic fibrosis in patients with chronic active hepatitis.15 Because of an HCV-related nonspecific inflammatory process that induces hepatocyte proliferation associated with an increase in alanine aminotransferase levels, patients with high inflammatory and proliferative activity are more prone to progress to HCC.16 Aflatoxin Aflatoxin is produced by Aspergillus flavus and A. parasiticus and is found in food such as peanuts and

Wilson’s disease is a heritable disease with mutations in the gene ATP7B and alterations in plasma copper circulation and its excretion in bile. Excessive free copper in the circulation can provoke cytoplasmic cell injury, cirrhosis, and sometimes HCC. 12 Nonalcoholic fatty liver disease (NAFLD) NAFLD affects 10-24% of the population in various countries. 17 The prevalence increases in high-risk groups, reaching 70-86% in obese and/or diabetic patients.18 Nonalcoholic steatohepatitis (NASH) is estimated to occur in 10% of NAFLD patients. NASH has been posited as a possible cause of cryptogenic cirrhosis.7 Patients with cryptogenic cirrhosis also develop HCC.

RECOMMENDATIONS 1. Governmental health agencies must recommend policies to prevent HCV/HBV transmission, to encourage a healthy lifestyle to prevent obesity and alcohol abuse (Class 1, Level A), and to establish measures to control metabolic conditions such as diabetes and obesity (Class 3, Level B).


PREVENTION Prevention of HCC can be classified as: a) primary, implying prevention of the development and progression of liver diseases; b) secondary, implying prevention of premalignant conditions such as cirrhosis; and c) tertiary, implying prevention of HCC reappearance after curative treatment. HCC prevention requires the identification of risk factors, the mechanisms involved in hepatocarcinogenesis, and the potential therapeutic agents (chemoprevention). As a general rule, patients with liver diseases progressing to cirrhosis are at increased risk of HCC; thus, it is paramount to prevent or treat liver diseases to modify the incidence of HCC. Effective treatment of CLDs may halt disease progression and prevent cirrhosis development. HCC prevention may be achieved through general preventive measures applicable to most CLDs or through specific treatment of primary liver disease. Primary prevention The single most important measure in the prevention of HCC is to prevent HBV or HCV infection.19 HBV infection can be prevented through HBV vaccination of infants and sexually active adults.20,21 Prevention of HBV and HCV transmission by blood contamination in medical settings can be achieved by testing blood products; using disposable needles, syringes, or other devices that can become contaminated by blood or serum; adequate cleansing and sterilization of endoscopic equipment; wearing gloves to handle wounds and blood products; avoiding multiple-use injectable vials; and following general recommendations to avoid transmission from viremic patients to health care workers.19,22 Educational and needle- and syringe-exchange programs for injecting drug users have also proven effective in reducing hepatitis infection. Secondary prevention

, 2014; 13 (Supl. 1): s4-s40

s9

remains elevated after therapy-induced suppression of HBV DNA in patients with cirrhosis; in a previous study, the difference in HCC incidence between lamivudine- and placebo-treated groups became evident after 18 months.19,26 Treatment with more effective antiviral therapies that include the newer, more potent antivirals that are effective against viral strains with greater drug resistance, such as entecavir and tenofovir, appears to also reduce HCC risk in patients with chronic hepatitis B.27,28 In addition, case-control and cohort studies of noncirrhotic chronic hepatitis B patients suggest that antiviral therapy can reduce HCC when treatment is delivered early, although the level of evidence remains low.29 Treatment of chronic hepatitis C More than 90% of hepatitis C patients with cirrhosis develop HCC. Thus, prevention of cirrhosis by successful elimination of HCV infection is likely to be a highly effective strategy for preventing HCC. Almost all studies to date have shown that HCC rates are highest in patients with cirrhosis and lower in those who respond to antiviral therapy that includes IFN;30,31 the rates are lowest in those exhibiting a sustained virological response (SVR).32 The preventive effect of antiviral therapy in patients with chronic hepatitis C may be even greater using pegylated IFN plus ribavirin because it achieves higher SVR rates than standard IFN.33,34 Even though HCC risk is markedly reduced in cirrhotic patients who exhibit a SVR, a long-term risk for HCC development remains for more than 5 years.35 It is important to mention that continued low dose of pegylated IFN therapy for those without a SVR fails to reduce the HCC risk.36 However, it is unknown whether treatment with triple therapy: pegylated IFN, ribavirin and protease inhibitors (Boceprevir and Telaprevir) or with the new direct acting antiviral may have an anticarcinogenic effect. Treatment of non-viral liver diseases

Treatment of chronic hepatitis B The viral load of HBV is a powerful independent risk factor for HCC development. 23 Interferon (IFN)-based therapy reduces HCC risk, particularly in the early stages of cirrhosis and by suppressing serum HBV DNA.24,25 Lamivudine reduces the risk of HCC in patients with HBV, particularly in the advanced fibrosis stages, including cirrhosis.23,26 However, it is not certain how long the risk of HCC

The percentage of HCC cases unrelated to either HBV or HCV varies between regions but is usually 10-20%.37 Such occurrences of HCC are related to alcoholic cirrhosis, NASH, genetic hemochromatosis, autoimmune liver diseases, and other infrequent diseases. Prevention of alcoholic liver disease by reducing excessive alcohol intake is a strategy to lower the incidence of HCC in countries where this is a preva-

s10


lent disorder. On the other hand, there is no evidence to date that the discontinuation of chronic excessive alcohol intake reverses the elevated HCC risk once cirrhosis is established, at least during the first 10 years (although some studies have suggested the opposite).19 Other lifestyle modifications, such as changes in diet, may prove beneficial in preventing HCC.38 Metabolic factors such as obesity and type 2 diabetes mellitus independently increase HCC risk in patients with hepatitis C or other causes of cirrhosis.39-41 Thus, prevention of obesity and its metabolic complications (insulin resistance, metabolic

, 2014; 13 (Supl. 1): s4-s40

syndrome, type 2 diabetes mellitus) should reduce HCC incidence. There is evidence that treatment with metformin but not with other antidiabetic medications can reduce the risk of HCC in patients with type 2 diabetes mellitus.42-44 Statins may also reduce HCC incidence independently of the cause of primary liver disease.45-47 The treatment of hemochromatosis is particularly suitable for HCC prevention because early treatment of hepatic iron overload prevents fibrotic liver disease and its complications. However, phlebotomy therapy at the stage of advanced fibrosis is ineffective in preventing HCC.48,49

RECOMMENDATIONS 1. The most important preventive strategy against HBV-related HCC is adoption of universal hepatitis B vaccination (Class 1, Level B). 2. All countries should prioritize efforts to adopt extended infant-immunization schedules that include hepatitis B vaccination and that ensure that coverage of these programs extends to all communities (Class 1, Level B). 3. Testing blood products for HBV and HCV is an essential strategy for preventing HCC related to chronic viral hepatitis (Class 1, Level A). 4. Adoption of universal precautions to avoid transmission of blood-borne viruses in health care settings is advocated as another effective measure to reduce HCV-related HCC (Class 2, Level C). 5. Effective antiviral therapy for chronic hepatitis B is a very important measure for preventing HCC (Class 2, Level B). 6. Effective antiviral therapy for chronic hepatitis C (SVR, normalization of alanine aminotransferase) is a very important measure for preventing HCC (Class 1, Level B); however, HCC risk is not removed entirely in patients with underlying cirrhosis (Class 2, Level C). 7. Preventing alcoholic liver disease should prevent some cases of HCC; dietary modifications should also be considered (Class 2b, Level C). 8. Adequate treatment of obesity and type 2 diabetes may also prevent some cases of HCC (Class 2, Level A). 9. Early detection of hemochromatosis by genetic screening for affected family members and serum studies of iron stores is important because iron overload correction by venesection prevents cirrhosis and the development of HCC (Class 2, Level A).


EARLY DETECTION IN DECOMPENSATED CIRRHOSIS HCC surveillance is a critical process for improving the survival of cirrhotic patients. Surveillance increases the survival of patients with Child-Pugh class A.50,51 In patients with Child-Pugh class B, survival was higher for patients under surveillance (17.1 months) compared with those whose HCC was detected incidentally (12.0 months).52 For patients with Child-Pugh class C, there was no significant difference in survival between surveillance and no surveillance.

, 2014; 13 (Supl. 1): s4-s40

s11

Surveillance in decompensated cirrhosis Periodic screening for HCC is recommended only in decompensated patients who are on a waiting list for liver transplantation.52 Cucchetti and colleagues performed a cost-effectiveness analysis of HCC surveillance in decompensated cirrhotic patients. After 10 years of follow-up, 6.6% were alive without HCC, 17.5% had been diagnosed with HCC, and 75.9% had died of cirrhosis-related causes without HCC. The short life expectancy in this specific group of patients made surveillance ineffective unless patients were on a waiting list for liver transplantation.53

RECOMMENDATION 1. HCC surveillance of patients with Child-Pugh class C or decompensated cirrhosis is recommended only for patients on a waiting list for liver transplantation (Class 2a, Level B).

s12


EARLY DETECTION IN COMPENSATED CIRRHOSIS Early HCC detection is paramount for providing effective treatment to compensated cirrhotic patients.54 In cirrhotic patients, early HCC detection has proven to increase the 2- and 5-year survival.55 Surveillance There are two classic screening tools for early detection: α-fetoprotein (AFP) level and ultrasound. Although a recommendation has been

, 2014; 13 (Supl. 1): s4-s40

made to use both strategies at 6 months, 54 a systematic review found that ultrasound as an isolated strategy is superior. 56 It has now been established that measuring the AFP level provides no extra benefit for the early detection in patients with cirrhosis. 57 It is important to assure the quality of both ultrasound equipment and radiologists to detect early lesions.58 When access to quality ultrasound is limited, AFP may be considered.59 New serological biomarkers might improve the early diagnosis of HCC, particularly Golgi protein 73, but further studies are required.60

RECOMMENDATIONS 1. In cirrhotic patients, ultrasound should be performed every 6 months (Class 1, Level A). 2. If quality ultrasound is not available, AFP level may be considered as a biomarker (Class 2, Level B).


EARLY DETECTION IN HEREDITARY (HH) HEMOCHROMATOSIS, NON-CIRRHOTIC HBV PATIENTS, AND FAMILIAL HISTORY OF HEPATOCELLULAR CARCINOMA Cirrhosis is the main risk factor for HCC. 61-64 Less common causes include HH, chronic hepatitis B without cirrhosis, alpha-1 antitrypsin deficiency, aflatoxin exposure, autoimmune hepatitis, some porphyrias, and Wilson’s disease. 64 Family history of hepatic cancer is also an important risk factor; family clusters of HCC have been frequently reported in Asian countries and less often in Europe or America.65,66 In these high-risk groups ultrasound-based HCC screening has proven to improve mortality.67 Hereditary hemochromatosis (HH) Chronic hepatic deposition of iron in HH leads to fibrosis, cirrhosis, and finally HCC. 68 The iron overload in the liver causes dysfunction of intracellular organelles such as the mitochondria, microsomes, lysosomes, peroxisomes, and endoplasmic reticulum, leading to cellular dysfunction and hepatocellular injury. Iron-induced DNA damage has been also demonstrated in both animal and hepatocyte culture models of iron overload.69 Cirrhosis is the most important adverse prognostic factor in HH, with a 5-year survival in untreated patients as low as 50%. 70 Patients with cirrhosis have 100- to 200-fold increased risk of developing HCC. HCC accounts for about 30% of HH-related deaths. Adequate management of iron stores significantly decreases, without eliminating, the risk of HCC development. Therefore, patients with cirrhosis, independent of phlebotomy treatment, should continue to be screened for HCC following apheresis procedures.70,71

, 2014; 13 (Supl. 1): s4-s40

s13

Non-cirrhotic chronic hepatitis B and hepatocellular carcinoma Chronic hepatitis B patients are at risk of HCC even in the absence of cirrhosis. HCC incidence in noncirrhotic HBV carriers ranges from 0.25% to 0.5% per year in Asia and Africa, and from 0.1% to 0.4% per year in Europe and America.72,73 The mechanisms involved in the progression to HCC in chronic hepatitis B patients are not known. Host-virus interactions in infected hepatocytes and cells involved in the inflammatory response to HBV infection could explain the progression to HCC. An alternative mechanism considers the oncogenic potential of HBV through DNA integration into the genome of liver cells.74,75 Although the mechanisms are not clear, some characteristics of the infection are important predictors of HCC,76 such as hepatitis B e antigen seropositivity,77 genotype C,74 and high viral load. Familial history of hepatocellular carcinoma Familial aggregation of HCC has been reported frequently in China where HBV infection is common. Familial aggregations have also been reported in other populations, although less frequently.66,78 Family history of HCC has been found to increase HCC risk even in persons with no hepatitis B or C infection.65,79 People with a family history of liver cancer have a two- to threefold increase in HCC risk, independent of the presence of chronic hepatitis B or C. This risk increases further in the presence of hepatitis B surface antigen and/or anti-HCV positivity to a 70-fold increased HCC risk.65 Some studies have suggested that a recessive inheritance model may play a role in familial HCC.

RECOMMENDATIONS 1. HCC surveillance should be performed for patients with HH and Child-Pugh class A or B cirrhosis, as well as those awaiting liver transplantation by experienced personnel using ultrasonography at 6-month intervals (Class 2, Level B). 2. Surveillance for HCC in noncirrhotic HBV carriers should be performed using ultrasonography at 6-month intervals (Class 1, Level B). 3. Surveillance for HCC in people with familial history of HCC, even in the absence of viral hepatitis B or C infection, should be performed using ultrasonography at 6-month intervals (Class 1, Level B).

s14


, 2014; 13 (Supl. 1): s4-s40

EARLY DETECTION IN NON-CIRRHOTIC PATIENTS

rhotic patients and may not reach the threshold required to initiate surveillance.82

The decision to initiate a noncirrhotic patient into a surveillance program for early HCC detection is driven by the HCC risk level. The recommended cutoff of annual incidence above which surveillance should be initiated is based on expert opinion and cost-benefit models, and can thus vary according to the underlying condition.80

Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH)

Hepatitis C Patients with chronic hepatitis C without cirrhosis are at risk of HCC development. Unfortunately, evidence about the incidence of HCC in this group is still too limited to recommend a surveillance program. Surveillance is deemed cost-effective if the expected HCC risk exceeds 1.5% per year in patients with hepatitis C.81 According to the HALT-C trial in noncirrhotic patients, the cumulative incidence rates of HCC at 3, 5, and 7 years were 1.4%, 2.9%, and 6.8%, respectively, with similar values for patients receiving pegylated IFN. These data confirmed that HCC can occur in noncirrhotic chronic HCV patients, although the incidence is lower than in cir-

For surveillance to be cost-effective in noncirrhotic patients with NAFLD, the HCC incidence must exceed 1.5% per year.83 A significant number of noncirrhotic individuals with NAFLD or NASH develop HCC, raising the possibility that NAFLD/NASH constitutes a risk factor for HCC independent of cirrhosis.84,85 A recent systematic review performed to evaluate the association between NAFLD/NASH and HCC concluded that the increased HCC risk in this setting seems to be predominantly limited to patients with cirrhosis. 86 Therefore, no surveillance program for NAFDL/NASH in noncirrhotic patients should be implemented under the current state of evidence. Other chronic liver disease (CLDs) There is a paucity of data to support a surveillance program for noncirrhotic patients with CLDs such as autoimmune liver disease, alpha-1 antitrypsin deficiency, Wilson’s disease, or HH.87-89

RECOMMENDATIONS 1. In noncirrhotic patients with chronic hepatitis C, the benefits of surveillance are uncertain (Class 2b, Level B). 2. HCC surveillance is not recommended for noncirrhotic patients with NAFLD/NASH or other CLDs (Class 3, Level A).


DIAGNOSIS Over the past decade, HCC survival has improved by more than 20%, largely because of advances in early diagnosis.90 Screening and surveillance of patients at increased risk of HCC are cost-effective and have been proven to reduce mortality.91 However, adherence to surveillance is less than 60%, 92 limiting the impact of this strategy. Non-invasive diagnosis Currently, HCC is diagnosed using contrast-enhanced dynamic imaging methods, either computed tomography (CT) or magnetic resonance imaging (MRI). Comparison of CT and MRI show the latter to be superior (sensitivity 78 vs. 84%; specificity 77 vs. 84%, respectively), although the accuracy of MRI is only 33% in small lesions.92 Nodular lesions detected by imaging methods are classified in accordance with the International Consensus Group for HCC as follows.93 • Regenerative macronodules: not premalignant. • Low-grade dysplastic nodules (DNs): difficult to differentiate from regenerative macronodules. • High-grade DNs: most frequent precursor of HCC. • Small HCC: < 2 cm, can be of vaguely nodular appearance (early) or distinctively nodular pattern (progressive). Vascularization is a critical aspect in the evaluation of a DN because HCC tends to develop arterial vascularization that is independent from the portal system. HCC diagnostic accuracy increases when CT or MRI examination shows arterial wash-in in the nodule followed by venous wash-out.94,95 The arterial supply pattern helps to differentiate a DN from HCC,96,97 except when the DN reaches an intermediate degree of capilarization.98 Despite this limitation, the vascular pattern is pathognomonic for HCC.99 The diagnosis of small nodules (< 2 cm) is challenging because it is difficult to differentiate a DN from a small HCC. This differentiation is crucial because one-third of DNs are malignant and a timely diagnosis is critical to being able to offer a curative treatment.100 The specificity of an isolated dynamic imaging method in the diagnosis of small liver nodules is excellent when the vascular pattern of the lesion is typical, making it unnecessary to submit

, 2014; 13 (Supl. 1): s4-s40

s15

patients to other imaging methods to other imaging methods or biopsy as biopsy.101,102 MRI diagnosis is expected to improve through second-generation cellular contrast agents such as gadoxetic acid. Gadoxetic acid increases the diagnostic accuracy for HCC, but evidence about its usefulness in small lesions (< 2 cm) is limited. Nevertheless, even when second-generation contrast agents are used, it is difficult to differentiate high-grade DNs from HCC because of their similarities.103-105 The use of a diffusion-weighted technique may increase further the diagnostic accuracy of MRI.106 Contrast-enhanced ultrasonography is better than conventional ultrasound for diagnosing HCC. Findings such as hyperenhancement during the arterial phase and hypoenhancement during the late phase have a sensitivity of 88.8% and specificity of 100%.103 However, external validation and specific training are important concerns when using this diagnostic technique. The measurement of AFP as an HCC diagnostic test must be abandoned.94,95 The AFP level has no satisfactory cutoff point and low sensitivity and specificity.104,105 Only one-third of patients with liver nodules have AFP levels > 100 ng/mL.92,106 Invasive diagnosis Despite the use of imaging methods, nearly 30% of patients will need a biopsy to establish the final diagnosis.92 Nodule biopsy must be conducted only when dynamic imaging examination is inconclusive, particularly in small lesions measuring 12 cm. 107 Biopsy can be conducted through fine needle aspiration or core-cutting needle biopsy and may be difficult to perform depending on the location of the lesion or the coagulation status of the patient. Although a positive biopsy result settles the diagnosis, a negative one may not rule out a diagnosis of HCC. The sensitivity and specificity of liver biopsy are 100 and 75%, 100 and 100%, and 96 and 71% for nodules ≤ 2 cm, > 2 and ≤ 3 cm, and > 3 and ≤ 5 cm, respectively.108 Because nodules < 1 cm are difficult to characterize through biopsy and have a low probability of malignancy, a follow-up plan must be established that includes ultrasonography every 3 months. Biopsy complications are infrequent.109 The possibility of neoplastic cell seeding is close to 2.5% in large nodules110 and is expected to be lower in small nodules. The use of immunohistochemical panels does not increase the accuracy of the diagnosis.111

s16


, 2014; 13 (Supl. 1): s4-s40

RECOMMENDATIONS 1. For liver nodules >1 cm, a single dynamic imaging examination with typical findings is sufficient for HCC diagnosis. If findings are not typical or if the vascular pattern is not characteristic, a second imaging technique should be used (Class 1, Level A). 2. MRI that includes evaluation of the hepatic biliary phase using a second-generation contrast agent is useful in the diagnosis of HCC (Class 1, Level A). 3. Contrast-enhanced ultrasonography and AFP level are not recommended as a primary tool for diagnosis (Class 1, Level A). 4. Liver nodules >1 cm with inconclusive imaging results should be biopsied (Class 1, Level A). 5. Surveillance of liver nodules < 1 cm should be conducted every 3 months with ultrasonography (Class 1, Level B).


STAGING Staging systems are designed to predict the overall prognosis of patients with HCC, to classify patients according to the prognostic variables, to provide a common system to compare results of various clinical trials, and to guide treatment choices. In the past decades, several staging systems have been proposed,112 leading to improvement in survival as treatments are tailored to the specific stage of HCC. Various classifications have been adopted to stage HCC (Tables 3 and 4). Although some systems have been validated in specific settings and countries, no single staging system has been validated across the spectrum of HCC patients and treatment options. The difficulty in establishing a universal staging system resides in the confluence of HCC and cirrhosis because both the characteristics of the tumor and the degree of liver dysfunction contribute to the overall prognosis.113 Moreover, the heterogeneity of HCC around the world, which reflects underlying differences in epidemiological background, etiology, and risk factors, further increases the complexity in creating a common staging system. Attempts to improve the classification and prognostic capabilities for HCC are still evolving. The conventional staging systems for HCC, such as the Okuda stage114 or the TNM stage115 have been shown to have important limitations. New systems have been proposed, but only some have been validated in different settings. Based on common characteristics shared by several staging systems, the key factors that influence HCC prognosis and treatment options are solitary versus multifocal tumors, the presence of macrovascular invasion, ext-

s17

, 2014; 13 (Supl. 1): s4-s40

rahepatic disease, high serum AFP level, patient performance status, and the degree of hepatic impairment.112 The Barcelona Clinic Liver Cancer Group (BCLC) staging classification was developed by Llovet and colleagues in 1999.116 When following patients with unresectable and nontransplantable HCC randomized to placebo, they observed that vascular invasion and extrahepatic spread were independent predictors of mortality. This allowed HCC patients to be classified into different categories based in variables related to hepatic function, portal hypertension, bilirubin level, cancer-related symptoms, physical status, and tumor stage (size, number, presence of distant metastases, and vascular invasion). Most therapeutic clinical trials have used the BCLC system as the reference staging system.112 The BCLC classification links the stage of the disease to a specific treatment algorithm that correlate with life expectancy. Following the BCLC staging system (Table 3), patients may be classified according to the following staging. • Stage 0 or very early. Asymptomatic HCC patients with a single nodule < 2 cm without portal hypertension, well-preserved liver function (Child-Pugh class A), and good performance status, which may benefit from curative therapies, with > 80% survival at 5 years. Currently 5-10% of Western patients are diagnosed at this stage compared with 30% in Japan diagnosed through intensive surveillance programs. • Stage A or early. Asymptomatic patients with single nodule (2-5 cm) or three nodules ≤ 3 cm and Child-Pugh class A or B. These patients may also benefit from curative therapies (resection,

Table 3. The Barcelona Clinic Liver Cancer (BCLC) Group classification of hepatocellular carcinoma. Stage

PST*

Tumor stage

Okuda**

Portal hypertension

Total bilirubin

0 0 0 0 0 1-2

Single Single Single 3 5 cm multinodular Vascular invasion and/or metastasis Any stage

I I I I-II I-II I-II

No Yes Yes

Normal Normal Altered

Child-Pugh class

A

B C D

A1 A2 A3 A4

3-4

III

A-B A-B A-B C

*: The performance status test (PST) is based on the Eastern Cooperative Oncology Group performance scale: 0: asymptomatic. 1: symptomatic and fully ambulatory. 2: symptomatic and in bed < 50% of the day. 3: symptomatic and in bed >50% of the day. 4: bedridden. **: The Okuda staging system (I-III) takes into account the size of the tumor, presence of ascites, and albumin and bilirubin levels.

1985

2002

1999

1998

2002

2003

1999

2006

2008

2008

2013

Okuda

TNM

BCLC

CLIP

CUPI

JIS

GRETCH (French)

BALAD score

Bm-JIS

US prognostic nomogram

Eastern Staging System 1-5

Nomogram

0-7

6

A,B,C

0-5

7-12

0-6

O,A,B,C,D

I-IV

1,2,3

Stage

Albumin, bilirubin, ALT, presence of cirrhosis

No

Ascites, bilirubin, alkaline phosphatase Child-Pugh class Bilirubin, alkaline phosphatase Albumin, bilirubin Child-Pugh class

Child-Pugh

Child-Pugh class, bilirubin, portal hypertension

No

Ascites, bilirubin, albumin

Liver function

No

AFP

AFP, AFP-L3, DCP AFP, AFP-L3, DCP

No AFP or < 50% area of liver, and portal vein thrombosis

Tumor > or ≤ 50% of cross-sectional area of the liver Number of nodules, tumor size, presence of portal vein thrombosis and metastasis

Tumor staging


AFP: alpha-fetoprotein. PST: performance status test (based on the Eastern Cooperative Oncology Group performance scale: 0: asymptomatic. 1: symptomatic and fully ambulatory. 2: symptomatic and in bed ≤ 50% of the day. 3: symptomatic and in bed >50% of the day. 4: bedridden). DCP: des-gamma-carboxyprothrombin; AFP-L3: Lens culinaris agglutinin-reactive. AFP. ALT: alanine aminotransferase.

Year

Staging system

Table 4. Main prognostic staging systems for hepatocellular carcinoma and included variables.

s18 , 2014; 13 (Supl. 1): s4-s40


liver transplantation, or local ablation), with 5075% survival at 5 years. • Stage B or intermediate. Large multinodular HCC with Child-Pugh class A or B, with adequate performance status. These patients may benefit from chemoembolization, with a median survival of 20 months. • Stage C or advanced. Multinodular with portal invasion or extrahepatic spread. These patients may benefit from palliative treatments with new agents such as sorafenib, with a median survival of 11 months. • Stage D or terminal. Child-Pugh class C patients, with very poor life expectancy. Symptomatic palliative treatment is proposed, with a median survival of 3-4 months.

, 2014; 13 (Supl. 1): s4-s40

s19

The BCLC staging classification has been validated in the USA, Europe, and Taiwan and has been shown to have superior prognosis capabilities over a range of other classifications. The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver have endorsed the BCLC staging system because it can be used to guide the choice of treatment and estimate life expectancy, whereas other staging systems focus exclusively on predicting survival (Figure 1). 117,118 Thus, the BCLC system is now emerging as the standard staging system in Western populations. Other staging or scoring systems for HCC have been proposed, such as the GRETCH (Groupe d’Etude et de Traitement du Carcinome Hepatocellu-

HCC

Stage 0

Stage A-C

Stage D

PST 0, Child-Pug A

PST 0-2, Child-Pugh A-B

PST>2 Child-Pugh C*

Very early stage (0)

Early stage (A)

Intermediate stage (B)

Advance stage (C)

Terminal stage (D)

Single < 2 cm Carcinoma in situ

Single or 3 nodules ≤ 3 cm PS 0

Multinodular, PS 0

Portal invasion, N1, M1, PS 1-2

Single

3 nodules ≤ 3 cm

TACE

Sorafenib

Best supportive care

Target: 20% OS: 20 mo (45-14)

Target: 40% OS: 11 mo (6-14)

Target: 10% OS: < 3 mo

Portal pressure/billirubin Increased

Associated diseases

Normal

No

Yes

Resection

Liver transplantation (CLT/LDLT)

RF/PEI

Caurative treatment (30-40%) Median OS > 60 mo; 5-yr survival: 40-70%

Figure 1. The Barcelona Clinic Liver Cancer (BCLC) staging system and treatment allocation. HCC: hepatocellular carcinoma. M: metastasis classification. N: node classification. TACE: transcatheter arterial chemoembolization. Adapted from European Association for the Study of the Liver: EASL-EORTC Clinical Practice Guideline: Management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-46.

s20


laire) scoring system,119 the CUPI (Chinese University Prognostic Index) staging system,120 the Simplified Staging System,121 the CLIP (Cancer of the Liver Italian program) scoring system, the JIS (Japan Integrated Staging) staging system,122 and the Tokyo scoring system (Table 4).123 Most clinical studies from Japan have concluded that the JIS or the modified JIS staging system are the best syste-

, 2014; 13 (Supl. 1): s4-s40

ms to stage their HCC patients. On the other hand, studies from China, Korea, and Taiwan have favored either the TNM or CLIP as the best staging systems. Most studies from Western countries have favored either the BCLC or CLIP system as the best staging system for their patients.124-127

RECOMMENDATIONS 1. An adequate assessment of the prognosis of HCC should consider the tumor stage, liver function, and physical status of the patient. The impact of therapy should also be considered when estimating life expectancy (Class 1, Level B). 2. The BCLC staging system is recommended for prognostic prediction and treatment allocation (Class 1, Level B). This system can be applied to most HCC patients provided that specific considerations for special subpopulations (e.g., liver transplantation) are incorporated.


LIVER TRANSPLANTATION Resection and liver transplantation are curative surgical treatments for HCC. Liver transplantation removes both the tumor and the underlying cirrhosis, and represents the first-line treatment for cirrhotic patients. Unfortunately, there are no randomized clinical trials comparing surgical resection and liver transplantation for HCC treatment.128 For liver transplantation, it is paramount to carefully select the best candidates by taking into account tumor stage, liver function, functional status of the patient, availability of a liver graft, technical experience, and probably some biological characteristics.129 The BCLC staging system is the most widely accepted system for guiding treatment recommendations and is the preferred system for assessing the prognosis of these patients.130 Compliance with the Milan criteria is the main factor for determining the prognosis for liver transplantation in patients with HCC and cirrhosis,131-133 and has been integrated into the BCLC staging system,134,135 and the United Networks for Organ Sharing pretransplant staging for organ allocation in the USA.136 To be eligible, candidates should have an expected survival of at least 70% over 5 years with a recurrence rate < 15%.131 Both survival and recurrence are heavily dependent on tumor size as established by the Milan criteria (solitary tumor ≤ 5 cm in diameter, or ≥ 3 tumors, each ≤ 3 cm in diameter and no macrovascular invasion).132 According to a meta-analysis,133 the 5-year survival rate of patients with HCC meeting the Milan criteria (65-78%) is similar to the rate observed in patients with no tumor evidence (68-87%). Patients meeting the Milan criteria are also at lower risk for microvascular invasion and poorly differentiated tumor. When exceeding the Milan criteria, the 5-year survival rate could be as low as 46-60%.

, 2014; 13 (Supl. 1): s4-s40

s21

An expanded version of the Milan criteria was tested at the University of California, San Francisco, with patients with a solitary tumor ≤ 6.5 cm or ≤ 3 nodules with the largest lesion ≤ 4.5 cm and total tumor diameter ≤ 8 cm, experienced survival rates of 90% and 75.2%, at 1 and 5 years, respectively, versus a 50% 1-year survival for patients with tumors exceeding these limits.137 However, other studies have failed to validate these expanded criteria. Downstaging for transplantation Patients exceeding the Milan criteria might benefit from reducing pretransplantation tumor stage (downstaging) by locoregional treatment.137,138 According to a recent meta-analysis, downstaging HCC before liver transplantation in patients outside the Milan criteria improved the survival rates at 1, 3, and 5 years from 82 to 100%, 79 to 100%, and 55 to 94%, respectively.139 These survival rates are similar to those of patients within the Milan criteria.130 Although promising, the clinical application of downstaging should be considered carefully because there were important methodological limitations present in all studies included in this meta-analysis. Incorporation of serum alpha-fetoprotein as patient selection criteria for liver transplantation Previous studies have demonstrated that an elevated pretransplantation serum AFP level is an independent risk factor for HCC recurrence after liver transplantation, suggesting that AFP should be incorporated in the patient selection criteria.140-143 Several cutoff values (210, 400, and 1000 ng/mL) have been proposed, but to date none has been validated.144-147

RECOMMENDATIONS 1. Liver transplantation should be the first-line treatment for patients within the Milan criteria (single tumor ≤ 5 cm or ≥ 3 nodules ≤ 3 cm) and not suitable for resection (Class 1, Level A). 2. Liver transplantation is not currently recommended for patients not meeting the Milan criteria because further prospective evidence of its benefit is required (Class 2a, Level B). 3. Liver transplantation may be considered after successful downstaging to meet the Milan criteria (Class 2a, Level B). 4. Further studies are required to validate the pretransplantation cutoff for serum AFP level as a criterion for liver transplantation (Class 2a, Level B).

s22


RESECTION Resection is the best therapeutic option for HCC in cirrhotic and noncirrhotic patients with a solitary nodule tumor, preserved hepatic function, and no portal hypertension (< 10% of cases).148-152 Resection has shown good results with low perioperative mortality (0.8-3%) and up to 60% survival at 5 years.150,153-162 Selection of the ideal candidate for resection depends on the careful CT or MRI evaluation of tumor size, presence of satellite lesions, and vascular involvement. The evaluation of preoperative liver function can be assessed using the indocyanine green retention rate at 15 min, directly by evaluation of portal hypertension by measuring the hepatic venous pressure gradient (desirable, < 10 mmHg), or indirectly by the platelet count (desirable, ≥ 100,000/ μL). Patients without direct hepatic venous pressure gradient measurement but with confirmed esophageal varices, diuretic therapy to control ascites, and high bilirubin level should not be considered for resection.156-163 The surgical procedure must aim to obtain at least 2 cm margins through anatomic resection, except when this procedure compromises the healthy residual liver volume of a cirrhotic patient; in this

, 2014; 13 (Supl. 1): s4-s40

case, a minimum surgical margin is sufficient. Although anatomic resection remains controversial, the general trend is to perform it whenever possible, provided that the volume of the remaining parenchyma is not affected.163-168 Recurrence after resection Recurrence after surgical resection can be 70% within 5 years and is more likely to occur within the first 3 years. The main mechanisms of recurrence are primary tumor dissemination, intrahepatic metastasis, and development of new tumors (de novo HCC).148,169-176 Factors contributing to recurrence are vascular invasion, presence of satellite lesions, histological differentiation grade, and size of the primary node resected.150,155,170,175 Many attempts have been made to find an effective adjuvant or neoadjuvant therapy to reduce the risk of recurrence. Several studies have been performed in Eastern countries, especially with IFN in the postoperative period. However, despite a recent meta-analysis showing a decrease in HCC recurrence in patients with viral hepatitis, data are lacking to safely recommend this alternative.157,177-181 In cases of recurrence, the patient must be reassessed by BCLC staging.177,178,182-190

RECOMMENDATIONS 1. Resection should be considered for patients with a solitary nodule tumor and preserved liver function; the tumor size, presence of satellite lesions, and vascular involvement should be considered (Class 2a, Level B). 2. Patients with esophageal varices, diuretic therapy to control ascites, and high bilirubin level should not be considered for resection (Class 2a, Level B). 3. Resection margins should aim for > 2 cm margins, except in patients with reduced parenchymal reserve (Class 3, Level B).


ABLATION When resection or transplantation is not an option, locoregional therapy represents a viable alternative for patients with HCC confined to the liver. Tumor cell destruction can be achieved through chemical substance injection (e.g., ethanol, acetic acid, or boiling saline) or by modifying the temperature (e.g., radiofrequency, microwave, laser, or cryotherapy). Currently, radiofrequency ablation (RFA) is the first choice for local ablation, but ethanol injection remains an important tool. Although nonresectional locoregional therapies are not curative, they destroy some tumors while preserving nontumorous liver parenchyma and may thus serve as a bridge toward a more definitive therapy such as liver transplantation or as salvage treatment for postresection recurrence. Percutaneous ethanol injection (PEI) PEI is a well-established technique for nodulartype HCC. PEI achieves complete necrosis in 90% of tumors < 2 cm, 70% of tumors 2-3 cm, and 50% of tumors 3-5 cm.191,192 In patients with Child-Pugh class A, cirrhosis, and early stage tumors, PEI has a 5-year survival rate of 47-53%.193,194 The major limitation of PEI is the high local recurrence rate, which may reach 43% in lesions > 3 m. 195 It has been speculated that ethanol diffusion can be blocked by the intratumoral fibrotic septa or the tumor capsule, undermining its curative capacity (particularly in tumors > 2 cm). Another chemical ablation techni-

, 2014; 13 (Supl. 1): s4-s40

s23

que, percutaneous acetic acid injection, does not offer substantial advantages to PEI.196 The efficacy of percutaneous ablation is assessed by dynamic CT 1 month after therapy.191 Radiofrequency ablation (RFA) RFA is superior to PEI in patients with early stage HCC, particularly those with compensated liver disease (Child-Pugh class A). 197 RFA has 5-year survival rates up to 76% when used as frontline therapy in patients with resectable HCC assessed by the BCLC criteria; this survival rate is similar to that after surgical resection.192,198 In two randomized trials, RFA was as effective as surgical resection in terms of overall survival and recurrence-free survival but was less invasive and had fewer complications.199,200 Therefore, RFA may represent a viable option to surgical resection in very early stage patients; however, more evidence is required before RFA can be recommended as a competitive alternative to resection. RFA has several limitations and produces suboptimal results in patients with tumors > 3 cm or with a perivascular location.201 Complete tumor necrosis has been observed in < 50% of tumors > 3 cm because of heat loss caused by perfusion-mediated tissue cooling within the area ablated.201 To overcome these limitations, numerous refinements of ablation methods are under clinical testing, including laser ablation, microwave ablation, cryoablation, light-activated therapy, and irreversible electroporation.

RECOMMENDATIONS 1. The standard of care for patients with BCLC stage 0-A tumors not suitable for surgery is local ablation with RFA or PEI. Other ablative therapies, such as microwave or cryoablation, are still under investigation (Class 2a, Level B). 2. RFA is recommended in tumors < 5 cm, and PEI is recommended in cases where RFA is not technically feasible (around 10-15% of patients) (Class 1, Level A). 3. In tumors < 2 cm, BCLC 0, both techniques achieve complete responses in > 90% of patients and produce a good long-term outcome. Whether they can be considered as competitive alternatives to resection is uncertain (Class 1, Level C).

s24


CHEMOEMBOLIZATION Curative therapies for HCC are available for about 30% of patients. Chemoembolization is an alternative for most patients, particularly those who are not candidates for resection, liver transplantation, or percutaneous ablation. Chemoembolization is the direct delivery of a chemotherapeutic agent into the tumor followed by an embolizing agent. Overall, arterial embolization increases the 2-year survival rate to 41% compared with 27% in control patients. However, embolization alone may not increase survival, and the treatment may require the addition of a chemotherapeutic agent. Patients receiving cisplatin or doxorubicin along with arterial embolization had a 58% better survival rate at 2 years compared with conservative management (odds ratio (OR) = 0.42; 95% confidence interval (CI) 0.20-0.88), a benefit not observed with embolization alone (OR = 0.59; 95% CI 0.291.20).202 There are some important predictors for improved overall survival after chemoembolization such as BCLC stage (A and B vs. C, hazard ratio (HR) = 3.58), Child-Pugh classification (A vs. B, HR = 2.34), tumor size (< 4 cm vs. ≥ 4 cm, HR = 2.58), and distribution (unilobar vs. bilobar HR = 2.11).203 Further research is needed particularly regarding the benefits of embolization in patients with portal vein invasion.204 Microsphere and bead embolization Microsphere embolization represents a promising alternative to standard chemoembolization. Patients treated with microspheres exhibited an improved overall survival (HR 0.73; 95% CI 0.60-0.88) and longer time to progression (HR 0.61; 95% CI 0.41-0.89) compared with patients receiving stan-

, 2014; 13 (Supl. 1): s4-s40

dard chemoembolization. Limited data suggest more benefits in patients treated with 32P glass microspheres than with yttrium 90 microspheres.205 In a similar manner, doxorubicin-eluting bead transarterial chemoembolization induced better 2- and 3-year survival rates compared with standard chemoembolization (2-year survival OR = 0.64, 95% CI 0.460.89; 3-year survival OR = 0.61, 95% CI 0.47-0.80).206 Preoperative transcatheter arterial chemoembolization Preoperative transcatheter arterial chemoembolization is considered an alternative treatment for preventing recurrence after hepatectomy. However, a large cohort study207 and a meta-analysis of nonrandomized studies have shown no benefit of this strategy to the 5-year overall survival (OR = 0.85; 95% CI 0.59-1.22) or the 5-year disease-free survival (OR = 1.19; 95% CI 0.93-1.53).208 Combination therapy Combination therapy seeks to provide further benefits by combining an ablative therapy, such as RFA, with standard chemoembolization. A recent meta-analysis showed that combination therapy had better 1- to 5-year and overall survival compared with monotherapy. However, when compared with standard chemoembolization, the combination therapy improved the 1-, 3-, and 5year survival rates but failed to significantly improve the 2-year and overall survival rates. 209 More randomized controlled trials are required to evaluate further the potential advantages of combination therapy over standard chemoembolization.

RECOMMENDATIONS 1. Chemoembolization should be considered for patients with BCLC stage B without portal invasion (Class 1, Level A). 2. The use of doxorubicin-eluting beads or yttrium 90 microspheres shows benefits over standard chemoembolization. However, the cost of these alternatives requires more research (Class 1, Level A). 3. Preoperative transcatheter arterial chemoembolization should not be considered as the standard of care (Class 1, Level A).


SYSTEMIC THERAPIES HCC diagnosed at an advanced stage or with progression after locoregional therapy has a poor prognosis because of the tumor itself and the underlying liver disease.210,211 Systemic therapeutic agents are an option, although to date, only sorafenib has shown positive results under randomized controlled conditions.212,213 Sorafenib Sorafenib is a small molecule that inhibits tumor cell proliferation and angiogenesis while increasing apoptosis. It acts by inhibiting the serine/threonine kinases Raf-1 and B-Raf, and by blocking the vascular endothelial growth factor receptors 1, 2, and 3 as well as the platelet-derived growth factor β receptors. Data on the efficacy of sorafenib come from the SHARP (Sorafenib HCC Assessment Randomized Protocol) and the Asia-Pacific randomized controlled trials, which involved patients with wellpreserved liver function (Child-Pugh class A) and HCC BCLC-C.212,213 In the SHARP trial, patients received sorafenib 400 mg b.i.d. or placebo; the median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group. Sorafenib was also superior to placebo for the time to radiological progression (5.5 vs. 2.8 months).212 In the Asia-Pacific trial, hepatitis B was the main cause of HCC, and patients had a more advanced disease (ECOG 1-2 or metastatic cancer); the median overall survival was 6.5 months in the sorafenib group versus 4.2 months in the placebo group.213 The most common grade 3 drug-related adverse events reported were diarrhea (8-9%) and hand-foot skin reaction (8-16%); drug discontinuation because of adverse events occurred in 15% of patients under sorafenib and in 7% of patients under placebo. Sorafenib must be maintained until clinical progression is observed. Sorafenib was discontinued upon decreased performance status, liver dysfunction progression, or other evidence of clinical progression.212 The evidence for sorafenib use in Child-Pugh class B patients is scarce because >95% of the patients with the SHARP and Asia-Pacific trials were Child-Pugh class A.212,213 Cohort studies analyzing Child-Pugh class B patients reported a similar frequency and profile of adverse events as in ChildPugh class A patients; however, the Child-Pugh class B patients experienced a higher frequency of both drug discontinuation (38% vs. 24%) and se-

, 2014; 13 (Supl. 1): s4-s40

s25

vere adverse events (15% vs. 8%). 214-217 Overall, the evidence suggests that sorafenib may be a safe option for Child-Pugh class B patients;214-217 however, at present, there are insufficient data to recommend its use. Resistance of HCC to sorafenib is a major concern. The exact mechanisms by which sorafenib acts upon HCC and the potential pathways to resistance are largely unknown. No other agent has proven to be efficacious in improving survival in a phase III trial, and no alternative treatment exists for patients with acquired resistance or intolerance to sorafenib.212,218 Several agents are currently in phase II and III development including tivantinib,219 brivanib,220 erlotinib and bevacizumab,221 and everolimus.222 In addition, the role of molecularly targeted therapy in combination with transcatheter arterial chemoembolization in earlier stages of the disease or as adjuvants after potentially curative approaches is under investigation.223-227 The ongoing international STORM (Sorafenib as Adjuvant Treatment in the Prevention of Recurrence of Hepatocellular Carcinoma) trial aims to investigate the role of sorafenib in reducing the chance of tumor recurrence following radical therapy; no results have been published yet. Other systemic therapies Doxorubicin, either in combination with other agents or as a single treatment, is the most commonly studied form of HCC chemotherapy. Doxorubicin has failed to improve survival in patients with advanced HCC. A large multicenter phase III trial of 445 patients with HCC investigated the use of doxorubicin or nolatrexed to improve survival, but the results were disappointing to the extent that further exploration of the use of nolatrexed in HCC treatment was no longer recommended.228 The use of doxorubicin versus the combination of cisplatin, IFNα-2b, doxorubicin, and fluorouracil was investigated in a randomized controlled trial involving 188 patients.229 No statistically significant difference in overall survival was observed, despite better response rates in the combination group compared with the doxorubicin group (20.9% and 10.5%, respectively). However, the combination of cisplatin, IFNα-2b, doxorubicin, and fluorouracil was associated with a higher rate of myelotoxicity. IFNs have immunomodulatory and antiproliferative effects on tumor cells and have been investigated in HCC. In one randomized study, IFNs were repor-

s26


ted to be superior to doxorubicin in terms of survival, tumor response, and toxicity in patients with HCC.230 However, IFN treatment for HCC requires further investigation. Estrogen receptors have been

, 2014; 13 (Supl. 1): s4-s40

found in HCC tumors, triggering the investigation of tamoxifen as a possible systemic treatment for HCC. However, the results from the randomized controlled trials involving tamoxifen were discouraging.231-234

RECOMMENDATIONS 1. Sorafenib is the standard systemic therapy for HCC in patients with Child-Pugh class A underlying cirrhosis and advanced tumor (BCLC stage C) or tumor progressing after locoregional therapy (Class 1, Level A). 2. There is no alternative treatment for patients with intolerance or failure to respond to sorafenib (Class 2, Level B). 3. Other systemic therapies are not recommended (Class 2a, Level A).


, 2014; 13 (Supl. 1): s4-s40

s27

PALLIATIVE CARE

Jaundice

Palliative care is the comprehensive care for a patient with a terminal illness. It has three main objectives: control symptoms related to the disease or the treatment, improve quality of life, and provide psychosocial and spiritual support to both the patient and family. 235 Most patients with HCC are diagnosed in an advanced stage requiring a multidisciplinary approach to palliative care.236 However, scientific evidence regarding the best approaches to palliative care in HCC is lacking.

Jaundice is an important sign in patients with HCC with or without biliary obstruction. In HCC patients with jaundice and no biliary obstruction, it is important to identify the treatable and reversible causes of jaundice such as reactivation of viral hepatitis or drug-induced or alcoholic hepatitis. In HCC patients with obstructive jaundice, it is important to first stabilize the patient, drain the bile duct obstruction, and control tumor bleeding and then to evaluate tumor resectability. Depending on the degree of biliary obstruction and general condition of the patient, these two steps may be performed in one or two phases.242 In patients with severe jaundice, biliary obstruction must be released by endoscopic retrograde cholangiopancreatography with biliary stent placement or through percutaneous transhepatic drainage. Percutaneous drainage is the best method to resolve the biliary obstruction because the tumor may be friable and may disseminate small fragments into the bile duct and clog the drains. In the presence of hemobilia, it is important not to confuse intrabiliary tumors with extensive intrabiliary blood clots. After treatment of the hemobilia, the endoscopic retrograde cholangiopancreatography should be repeated to delineation of the extent of the tumor. In the presence of profuse hemobilia, embolization through selective hepatic angiography is recommended. In HCC patients with jaundice, palliative drainage should be performed to improve quality of life.243

Abdominal pain Abdominal pain is the most common symptom in patients with HCC and may be related to the size of the tumor or to metastatic lesions. According to the World Health Organization guidelines, pain management with opioids is recommended, although this recommendation is not based on clinical trial evidence.237 Preliminary information suggests that opioids have greater bioavailability in patients with HCC (64.8%) or liver metastases (62.1%) than in controls (16.8%).238 Fatigue Patients with HCC frequently report fatigue. Fatigue is a multifactorial symptom that involves pain, emotional stress, sleep disturbance, anemia, nutritional deficiency, deconditioning, and comorbidities.239 Pharmacological interventions are directed toward altering the factors associated with fatigue such as the use of erythropoietin in patients with chemotherapy-induced anemia, antidepressants if depression is suspected to be the cause of fatigue, or psychostimulants to increase the level of energy. Weight loss Weight loss affects 54-80% of HCC patients in the terminal stage and occurs mainly because of the anorexia-cachexia syndrome. Although the diagnosis of anorexia-cachexia syndrome is based mainly on weight loss and anorexia, other parameters such as hypoalbuminemia, fatigue, chronic nausea, decreased caloric intake, or decreased muscle mass and body fat are also strong indicators of the syndrome. Megestrol (320 mg/day) has been shown to reduce the loss of appetite, nausea, and vomiting while improving quality of life in patients with the anorexiacachexia syndrome.240-242

Itching Itching secondary to cholestasis can be treated using cholestyramine to decrease the enterohepatic circulation of bile acids. Other general care measures include emollients to keep the skin hydrated and reduce itching, and use of unscented soap to prevent skin irritation and relieve symptoms.244 Variceal bleeding Patients with acute variceal bleeding and unresectable HCC experience high rates of recurrent bleeding and mortality. 245,246 Endoscopic variceal ligation is highly effective in controlling bleeding and has proven to be superior to sclerotherapy. 247,248 Portal vein thrombosis and tumors in both lobes are related to the recurrence of bleeding. 249 The use of a transjugular intrahepatic portosystemic shunt is a palliative

s28


measure for the control of variceal bleeding and ascites. 250 Radiation therapy Palliative radiation therapy for liver tumors is indicated in patients experiencing abdominal pain and to reduce the symptoms caused by the mass effect or bone pain caused by metastasis to bone metastasis, the adrenal glands, lymph nodes, central nervous system, or soft tissues.251 Surgical resection is an effective treatment for patients with a small or single metastatic lesion. Other options are RFA, highintensity ultrasound, cryoablation, and tumor ablation with ethanol; all previous approaches have

, 2014; 13 (Supl. 1): s4-s40

shown limitations in treating multiple metastatic lesions. Stereotactic radiation is a new method for direct high-dose radiation aimed at a target volume. After stereotactic radiation, quality of life improves moderately and remains relatively stable, although depression, and the severity of symptoms such as fatigue, decreased appetite, nausea, and pain may remain.252 Psychosocial and spiritual support Psychosocial and spiritual support of the patient must be provided by a multidisciplinary team of physicians, nurses, pharmacists, social workers, and religious advisors to help patients and families.253

RECOMMENDATIONS 1. Palliative care should be provided to all patients with advanced HCC with no other therapeutic alternative (Class 1, Level C). 2. Primary symptoms should be treated with the less invasive alternatives. However, endoscopic procedures and radiotherapy may be used on a case-by-case basis (Class 1, Level C). 3. More research is needed in this understudied group of patients (Class 1, Level C).


HEPATOCELLULAR CARCINOMA IN THE NON-CIRRHOTIC LIVER In the general population, 15-20% of HCCs occur in the noncirrhotic liver,254 but these figures vary from 7% to 54% between geographic areas and according to the liver disease etiology.255-260 Noncirrhotic HCC affects patients with no evidence of liver disease or with inflammatory, fibrotic, or degenerative liver diseases (e.g., chronic viral hepatitis, HH, and NASH). Fewer than 10% of noncirrhotic HCC cases occur with no evidence of liver disease; these cases are frequently associated with genotoxic agents such as aflatoxins, although an uncertain proportion arise through transformation of hepatic adenomas.255,261 Noncirrhotic HCCs follow a bimodal distribution with respect to age, with the first peak of incidence in the second decade of life (when there is no difference in gender distribution and the fibrolamellar variant is the main form of presentation), and the second peak around the sixth decade of life.255,262 Surveillance Individuals with a family history of HCC are at two- to threefold increased risk of developing HCC and should be included in a surveillance protocol independent of their hepatic health status.263 Patients with HBV infection and a family history of HCC are at a particularly high risk for HCC because of the synergistic effect of these two factors.264 HCC related to hepatitis C can be found in the noncirrhotic liver.265 In the HALT-C trial, the cumulative 5-year HCC incidence among patients with cirrhosis was 7.0% compared with 4.1% in those with bridging fibrosis.266 Among 720 HCC cases involving a noncirrhotic liver, almost 30% were related to HCV

, 2014; 13 (Supl. 1): s4-s40

s29

infection.255 Considering that the transition from advanced fibrosis to cirrhosis cannot be defined accurately, the EASL-EORT guidelines recommend surveillance for patients with bridging fibrosis, although its cost-effectiveness is yet to be established.267 Evidence about the relationships between noncirrhotic HCC, NASH, autoimmune liver disease, HH, and alpha-1 antitrypsin deficiency is still limited.267 An increasing number of reports of HCC in patients with a noncirrhotic liver and NASH have been published in recent years.268,269 Obesity and diabetes prevention represents the best longterm strategy for avoiding NASH-related HCC,270 although strong evidence for the efficacy of such interventions in preventing HCC has not been reported. Treatment There are two therapeutic lines to follow in patients with noncirrhotic HCC. The first line is liver resection, which has an overall survival rate of 2581% and tumor recurrence rate of 30-73%.271 Another approach is liver transplantation, either as primary or as a rescue treatment following recurrence after resection.272 Only patients free of pathological macrovascular invasion and lymph node involvement should be considered for liver transplantation. The 1- and 5-year overall and tumor-free survival rates were 84% and 49% for primary transplantation and 76% and 43% for rescue transplantation, respectively.273 A 1999 systematic review suggested that fibrolamellar HCC is a more favorable indication for orthotopic liver transplantation (40% 5-year survival rate) than is nonfibrolamellar HCC (11.2% 5-year survival rate) in patients with no underlying liver disease.274

RECOMMENDATIONS 1. HCC surveillance in noncirrhotic patients is indicated every 6 to 12 months using ultrasonography in: • Patients with a family history of HCC (Class 2, Level B), • Patients with HBV and active hepatitis (Class 2, Level B), • Patients with HCV with bridging fibrosis in the liver biopsy (Class 2b, Level B). 2. Surgery with lobular resection is the first-line treatment for HCC in the noncirrhotic, nonfibrotic liver (Class 1, Level B). 3. In patients for whom resection is not indicated, liver transplantation can be offered to those affected by fibrolamellar HCC (Class 1, Level B). Transplantation in nonfibrolamellar patients is indicated only if there is no macrovascular invasion or lymph node involvement (Class 2b, Level B).

s30


, 2014; 13 (Supl. 1): s4-s40

Primary childhood liver tumors are rare, affecting 5 of 10,000,000 children younger than 19 years of age. HCC is typically diagnosed in children aged 10 years and older (75%). Fibrolamellar HCC is diagnosed at older ages and receives surgical treatment more frequently than does nonfibrolamellar HCC.275 Despite important advances in surgical treatment, fewer than 30% of affected children are cured. Results obtained through resection with partial hepatectomy remain dismal because of the high recurrence rate. Pediatric patients with unresected HCC remain largely unresponsive to chemotherapy and continue to have a very poor prognosis.

nale d’Oncologie Pédiatrique – Epithelial Liver Tumor Study Group trial 1 (SIOPEL-1) using preoperative chemotherapy with a combination of doxorubicin and cisplatin (PLADO), the overall survival at 5 years was 28% and event-free survival was 17%. In SIOPEL-2, 21 patients were treated with alternating cycles of cisplatin and carboplatin/doxorubicin; 18% had metastasis, 35% had extrahepatic extension/vascular invasion, and 53% had multifocal HCC. The 3-year overall survival was 28%. 280,281 A North American trial that compared PLADO against vincristine/cisplatin/5-fluorouracil found no statically significant differences in survival. 282,283 New drugs such as aflibercept (VEGF-Trap) are in phase I trials and have potential as new treatments.284

Treatment

Sorafenib

Resection and liver transplant

Sorafenib is a promising option for HCC treatment in children. The impact of sorafenib on survival of adult patients with advanced HCC has been tested in clinical trials and analyzed in a metaanalysis, leading to its approval as first-line systemic therapy.282,283,285-290 In children, the evidence is still scarce. In a retrospective analysis, 12 patients with HCC received chemotherapy treatment (PLADO) and sorafenib; six were in complete remission after 20 months, four of them were maintained on a PLADO/sorafenib/resection treatment and two required transplantation after local recurrence. Four of seven patients with an unresectable tumor had a partial response to PLADO/sorafenib, two were stabilized, and one progressed. Although promising, the use of sorafenib alone versus sorafenib/chemotherapy should be evaluated further.289

PEDIATRIC HEPATOCELLULAR CARCINOMA

Complete tumor resection is the cornerstone of HCC treatment; however, complete resection is achieved in only 25% of children. Pediatric patients undergoing tumor resection experience a significant increase in 5-, 10-, and 20-year survival compared with those who do not undergo resection,275 but the results are not as positive as those observed after orthotopic transplantation (53.4% 5-year survival for resection vs. 85.3% for orthotopic transplantation).276 The role of lymphadenectomy is not clear, but it may improve the prognosis of surgically treated patients.277 There is no consensus about which liver transplantation criteria should be used in children with HCC. The Milan criteria are used widely despite having been designed for adults. Limited nonrandomized evidence suggests that children not meeting the Milan criteria can be transplanted with no detectable difference in survival.278,279 Chemotherapy Chemotherapy has proven to be only partially useful in treating HCC. In the Société Internatio-

Arterial chemoembolization Indications for arterial chemoembolization in children are limited. The most significant indication should be the presence of tumors that remain unresectable after systemic chemotherapy to try to make the tumors resectable without the need for transplantation.291-293


, 2014; 13 (Supl. 1): s4-s40

RECOMMENDATIONS 1. Surgical resection is the best treatment option for HCC in children (Class 2, Level B). 2. Liver transplantation is an alternative. However, reliance on the Milan criteria to indicate eligibility for transplantation is unclear, and children not meeting the criteria may still benefit from transplantation (Class 2, Level B). 3. Chemotherapy may be considered in pediatric patients for whom surgical treatment is not viable. Further research is needed to evaluate this possibility (Class 2, Level B).

s31

s32


ABBREVIATIONS • • • • • • • • • • • • • • • • • • • • • • • • •

AFP: alpha-fetoprotein. BCLC: Barcelona Clinic Liver Cancer Group. CI: confidence interval. CLD: chronic liver disease. CT: computed tomography. CUPI: Chinese University Prognostic Index. DN: dysplastic nodule. EASL: European Association for the Study of the Liver. GRETCH: Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. HBV: hepatitis B virus. HCC: hepatocellular carcinoma. HCV: hepatitis C virus. HH: hereditary hemochromatosis. HR: hazard ratio. IFN: interferon. JIS: Japan Integrated Staging. MRI: magnetic resonance imaging. NAFLD: nonalcoholic fatty liver disease. NASH: nonalcoholic steatohepatitis. OR: odds ratio. PEI: percutaneous ethanol injection. PLADO: cisplatin and doxorubicin. RFA: radiofrequency ablation. SHARP: Sorafenib hepatocellular carcinoma Assessment Randomized Protocol. SVR: sustained virological response. REFERENCES

1. Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis 2010; 30: 3-16. 2. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 2013; 47(Suppl): S2-6. 3. Mendez-Sanchez N, Villa AR, Vazquez-Elizondo G, et al. Mortality trends for liver cancer in Mexico from 2000 to 2006. Ann Hepatol 2008; 7: 226-9. 4. Fassio E, Diaz S, Santa C, et al. Etiology of hepatocellular carcinoma in Latin America: a prospective, multicenter, international study. Ann Hepatol 2010; 9: 63-9. 5. Fassio E, Miguez C, Soria S, et al. Etiology of hepatocellular carcinoma in Argentina: results of a multicenter retrospective study. Acta Gastroenterol Latinoam 2009; 39: 47-52. 6. Osorio FM, Lauar GM, Lima AS, et al. Epidemiological aspects of hepatocellular carcinoma in a referral center of Minas Gerais, Brazil. Arq Gastroenterol 2013; 50: 97-100. 7. Motola-Kuba D, Zamora-Valdes D, Uribe M, MendezSanchez N. Hepatocellular carcinoma. An overview. Ann Hepatol 2006; 5: 16-24. 8. Mendez-Sanchez N, Aguilar-Ramirez JR, Reyes A, et al. Etiology of liver cirrhosis in Mexico. Ann Hepatol 2004; 3: 30-3. 9. Marrero JA. Hepatocellular carcinoma. Curr Opin Gastroenterol 2003; 19: 243-9.

, 2014; 13 (Supl. 1): s4-s40

10. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295: 65-73. 11. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst 2005; 97: 265-72. 12. Bailey MA, Brunt EM. Hepatocellular carcinoma: predisposing conditions and precursor lesions. Gastroenterol Clin North Am 2002; 31: 641-62. 13. Kaplan DE, Reddy KR. Rising incidence of hepatocellular carcinoma: the role of hepatitis B and C; the impact on transplantation and outcomes. Clin Liver Dis 2003; 7: 683714. 14. Raimondi S, Bruno S, Mondelli MU, Maisonneuve P. Hepatitis C virus genotype 1b as a risk factor for hepatocellular carcinoma development: a meta-analysis. J Hepatol 2009; 50: 1142-54. 15. Sangiovanni A, Prati GM, Fasani P, et al. The natural history of compensated cirrhosis due to hepatitis C virus: a 17year cohort study of 214 patients. Hepatology 2006; 43: 1303-10. 16. Tarao K, Rino Y, Ohkawa S, et al. Close association between high serum alanine aminotransferase levels and multicentric hepatocarcinogenesis in patients with hepatitis C virus-associated cirrhosis. Cancer 2002; 94: 1787-95. 17. El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans. Am J Gastroenterol 2001; 96: 2462-7. 18. Mendez-Sanchez N, Arrese M, Zamora-Valdes D, Uribe M. Current concepts in the pathogenesis of nonalcoholic fatty liver disease. Liver Int 2007; 27: 423-33. 19. Prevention of hepatocellular carcinoma in the Asia-Pacific region: consensus statements. J Gastroenterol Hepatol 2010; 25: 657-63. 20. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 1997; 336: 1855-9. 21. Chang MH, You SL, Chen CJ, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst 2009; 101: 1348-55. 22. Alter MJ. Healthcare should not be a vehicle for transmission of hepatitis C virus. J Hepatol 2008; 48: 2-4. 23. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295: 65-73. 24. Yang YF, Zhao W, Zhong YD, et al. Interferon therapy in chronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: a meta-analysis. J Viral Hepat 2009; 16: 265-71. 25. Miyake Y, Takaki A, Iwasaki Y, Yamamoto K. Meta-analysis: interferon-alpha prevents the recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma. J Viral Hepat 2010; 17: 287-92. 26. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 1521-31. 27. Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2013; 58: 98-107. 28. Singal AK, Salameh H, Kuo YF, Fontana RJ. Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther 2013; 38: 98-106.


29. Sung JJ, Tsoi KK, Wong VW, et al. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008; 28: 1067-77. 30. Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of hepatocarcinogenesis by interferon therapy. Ann Intern Med 1999; 131: 174-81. 31. Ikeda K, Saitoh S, Arase Y, et al. Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis. Hepatology 1999; 29: 1124-30. 32. Morgan RL, Baack B, Smith BD, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 2013; 158: 329-37. 33. Ogawa E, Furusyo N, Kajiwara E, et al. Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: a prospective, multicenter study. J Hepatol 2013; 58: 495-501. 34. Akuta N, Suzuki F, Seko Y, et al. Efficacy and anticarcinogenic activity of ribavirin combination therapy for hepatitis C virus-related compensated cirrhosis. Intervirology 2013; 56: 37-45. 35. Aleman S, Rahbin N, Weiland O, et al. A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C-associated liver cirrhosis. Clin Infect Dis 2013; 57: 230-6. 36. Bruix J, Poynard T, Colombo M, et al. Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C. Gastroenterology 2011; 140: 1990-9. 37. McGlynn KA, London WT. The global epidemiology of hepatocellular carcinoma: present and future. Clin Liver Dis 2011; 15: 223-43. 38. Turati F, Trichopoulos D, Polesel J, et al. Mediterranean diet and hepatocellular carcinoma. J Hepatol 2014; 60: 606-11. 39. Welzel TM, Graubard BI, Zeuzem S, et al. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology 2011; 54: 463-71. 40. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012; 10: 1342-59 e1342. 41. Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008; 371: 569-78. 42. Singh S, Singh PP, Singh AG, et al. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol 2013; 108: 881-91; quiz 892. 43. Zhang H, Gao C, Fang L, et al. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a metaanalysis. Scand J Gastroenterol 2013; 48: 78-87. 44. Chen HP, Shieh JJ, Chang CC, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 2013; 62: 606-15.

, 2014; 13 (Supl. 1): s4-s40

s33

45. Tsan YT, Lee CH, Ho WC, et al. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J Clin Oncol 2013; 31: 1514-21. 46. Singh S, Singh PP, Singh AG, et al. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 2013; 144: 323-32. 47. Chiu HF, Ho SC, Chen CC, Yang CY. Statin use and the risk of liver cancer: a population-based case-control study. Am J Gastroenterol 2011; 106: 894-8. 48. Elmberg M, Hultcrantz R, Ekbom A, et al. Cancer risk in patients with hereditary hemochromatosis and in their firstdegree relatives. Gastroenterology 2003; 125: 1733-41. 49. Allen KJ, Nisselle AE, Collins VR, et al. Asymptomatic individuals at genetic risk of haemochromatosis take appropriate steps to prevent disease related to iron overload. Liver Int 2008; 28: 363-9. 50. Yuen MF, Cheng CC, Lauder IJ, et al. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000; 31: 330-5. 51. Trevisani F, De Notariis S, Rapaccini G, et al. Semiannual and annual surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience). Am J Gastroenterol 2002; 97: 734-44. 52. Trevisani F, Santi V, Gramenzi A, et al. Surveillance for early diagnosis of hepatocellular carcinoma: is it effective in intermediate/advanced cirrhosis? Am J Gastroenterol 2007; 102: 2448-57; quiz 2458. 53. Cucchetti A, Trevisani F, Cescon M, et al. Cost-effectiveness of semi-annual surveillance for hepatocellular carcinoma in cirrhotic patients of the italian liver cancer population. J Hepatol 2012; 56: 1089-96. 54. Thompson Coon J, Rogers G, Hewson P, et al. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis. Health Technol Assess 2007; 11: 1-206. 55. Yuen MF, Lai CL. Screening for hepatocellular carcinoma: survival benefit and cost-effectiveness. Ann Oncol 2003; 14: 1463-7. 56. Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J Gastroenterol 2006; 101: 513-23. 57. Singal A, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009; 30: 37-47. 58. Choi JI, Kim PN, Jeong WK, et al. Establishing cutoff values for a quality assurance test using an ultrasound phantom in screening ultrasound examinations for hepatocellular carcinoma: an initial report of a nationwide survey in Korea. J Ultrasound Med 2011; 30: 1221-9. 59. Daniele B, Bencivenga A, Megna AS, Tinessa V. Alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma. Gastroenterology 2004; 127: S108-12. 60. Witjes CD, van Aalten SM, Steyerberg EW, et al. Recently introduced biomarkers for screening of hepatocellular carcinoma: a systematic review and meta-analysis. Hepatol Int 2013; 7: 59-64. 61. Jemal A, Bray F, Center MM, et al. Global cancer statistics. Cancer J Clin 2011; 61: 69-90. 62. Marrero JA, Fontana RJ, Su GL, et al. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002; 36: 1349-54.

s34


63. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010; 51: 1820-32. 64. Cabibbo G, Maida M, Genco C, et al. Causes of and prevention strategies for hepatocellular carcinoma. Semin Oncol 2012; 39: 374-83. 65. Yu MW, Chang HC, Liaw YF, et al. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. J Natl Cancer Inst 2000; 92: 1159-64. 66. Hassan MM, Spitz MR, Thomas MB, et al. The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States. J Hepatol 2009; 50: 334-41. 67. Yeh YP, Hu TH, Cho PY, et al. Evaluation of abdominal ultrasonography mass screening for hepatocellular carcinoma in Taiwan. Hepatology 2013 Aug 26. doi: 10.1002/ hep.26703. 68. Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54: 328-43. 69. Vecchi C, Montosi G, Zhang K, et al. ER stress controls iron metabolism through induction of hepcidin. Science 2009; 325: 877-80. 70. Niederau C, Fischer R, Purschel A, et al. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996; 110: 1107-19. 71. Falize L, Guillygomarc’h A, Perrin M, et al. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology 2006; 44: 472-7. 72. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48: 335-52. 73. Sanchez-Tapias JM, Costa J, Mas A, et al. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology 2002; 123: 1848-56. 74. Hadziyannis SJ. Natural history of chronic hepatitis B in Euro-Mediterranean and African countries. J Hepatol 2011; 55: 183-91. 75. Pollicino T, Saitta C, Raimondo G. Hepatocellular carcinoma: the point of view of the hepatitis B virus. Carcinogenesis 2011; 32: 1122-32. 76. Lok AS. Prevention of hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 2004; 127: S303-9. 77. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002; 347: 168-74. 78. Turati F, Edefonti V, Talamini R, et al. Family history of liver cancer and hepatocellular carcinoma. Hepatology 2012; 55: 1416-25. 79. Chen CH, Huang GT, Lee HS, et al. Clinical impact of screening first-degree relatives of patients with hepatocellular carcinoma. J Clin Gastroenterol 1998; 27: 236-9. 80. European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-43. 81. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020-2. 82. Lok AS, Everhart JE, Wright EC, et al. Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C. Gastroenterology 2011; 140: 840-9. e841. 83. Della Corte C, Colombo M. Surveillance for hepatocellular carcinoma. Semin Oncol 2012; 39: 384-98.

, 2014; 13 (Supl. 1): s4-s40

84. Ertle J, Dechêne A, Sowa JP, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Intern J Cancer 2011; 128: 2436-43. 85. Yasui K, Hashimoto E, Komorizono Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011; 9: 428-33. 86. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012; 10: 1342-59 e1342. 87. Deugnier YM, Guyader D, Crantock L, et al. Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases. Gastroenterology 1993; 104: 228-34. 88. Perlmutter DH. Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res 2006; 60: 233-8. 89. Polio J, Enriquez RE, Chow A, et al. Hepatocellular carcinoma in Wilson’s disease. Case report and review of the literature. J Clin Gastroenterol 1989; 11: 220-4. 90. Davila JA, El-Serag HB. Racial differences in survival of hepatocellular carcinoma in the United States: a population-based study. Clin Gastroenterol Hepatol 2006; 4: 104-10; quiz 104-105. 91. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004; 130: 417-22. 92. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008; 134: 1752-63. 93. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 2009; 49: 658-64. 94. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020-2. 95. European Association for the Study of the L, European Organisation for R, Treatment of C. EASL–EORTC Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-43. 96. Roncalli M, Park YN, Di Tommaso L. Histopathological classification of hepatocellular carcinoma. Dig Liver Dis 2010; 42(Suppl. 3): S228-34. 97. Hayashi M, Matsui O, Ueda K, et al. Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: evaluation by CT during intraarterial injection of contrast medium. Am J Roentgenol 1999; 172: 969-76. 98. Roskams T, Kojiro M. Pathology of early hepatocellular carcinoma: conventional and molecular diagnosis. Semin Liver Dis 2010; 30: 17-25. 99. Rimola J, Forner A, Tremosini S, et al. Non-invasive diagnosis of hepatocellular carcinoma ? 2 cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI. J Hepatol 2012; 56: 1317-23. 100. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698-711. 101. Sangiovanni A, Manini MA, Iavarone M, et al. The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010; 59: 638-44. 102. Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective valida-


103.

104. 105. 106.

107.

108.

109. 110.

111.

112. 113.

114. 115. 116. 117. 118.

119.

120.

tion of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008; 47: 97-104. Xu HX, Lu MD, Liu LN, et al. Discrimination between neoplastic and non-neoplastic lesions in cirrhotic liver using contrast-enhanced ultrasound. Br J Radiol 2012; 85: 1376-84. Forner A, Reig M, Bruix J. Alpha-fetoprotein for hepatocellular carcinoma diagnosis: the demise of a brilliant star. Gastroenterology 2009; 137: 26-9. Sherman M. Alphafetoprotein: an obituary. J Hepatol 2001; 34: 603-5. Hu B, Tian X, Sun J, Meng X. Evaluation of individual and combined applications of serum biomarkers for diagnosis of hepatocellular carcinoma: a meta-analysis. Int J Mol Sci 2013; 14: 23559-80. Serste T, Barrau V, Ozenne V, et al. Accuracy and disagreement of computed tomography and magnetic resonance imaging for the diagnosis of small hepatocellular carcinoma and dysplastic nodules: role of biopsy. Hepatology 2012; 55: 800-6. Colecchia A, Scaioli E, Montrone L, et al. Pre-operative liver biopsy in cirrhotic patients with early hepatocellular carcinoma represents a safe and accurate diagnostic tool for tumour grading assessment. J Hepatol 2011; 54: 300-5. Forner A, Ayuso C, Isabel Real M, et al. Diagnosis and treatment of hepatocellular carcinoma. Med Clin (Barc) 2009; 132: 272-87. Silva MA, Hegab B, Hyde C, et al. Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut 2008; 57: 1592-6. Tremosini S, Forner A, Boix L, et al. Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma. Gut 2012; 61: 1481-7. Llovet JM. Treatment of hepatocellular carcinoma. Curr Treat Options Gastroenterol 2004; 7: 431-41. Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 1985; 56: 91828. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362: 1907-17. Greene FL. The American Joint Committee on Cancer: updating the strategies in cancer staging. Bull Am Coll Surg 2002; 87: 13-15. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19: 329-38. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020-2. European Association for the Study of the L, European Organisation for R, Treatment of C. EASL–EORTC Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-43. Chevret S, Trinchet JC, Mathieu D, et al. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. J Hepatol 1999; 31: 133-41. Leung TW, Tang AM, Zee B, et al. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Ital-

121. 122.

123. 124.

125.

126.

127.

128.

129. 130.

131.

132. 133.

134. 135. 136. 137.

138.

, 2014; 13 (Supl. 1): s4-s40

s35

ian Program staging system: a study based on 926 patients. Cancer 2002; 94: 1760-9. Vauthey JN, Lauwers GY, Esnaola NF, et al. Simplified staging for hepatocellular carcinoma. J Clin Oncol 2002; 20: 1527-36. Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J Gastroenterol 2003; 38: 207-15. Tateishi R, Yoshida H, Shiina S, et al. Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients. Gut 2005; 54: 419-25. Ueno S, Tanabe G, Sako K, et al. Discrimination value of the new western prognostic system (CLIP score) for hepatocellular carcinoma in 662 japanese patients. Cancer of the Liver Italian Program. Hepatology 2001; 34: 529-34. Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an american cohort. Hepatology 2005; 41: 70716. Farinati F, Rinaldi M, Gianni S, Naccarato R. How should patients with hepatocellular carcinoma be staged? Validation of a new prognostic system. Cancer 2000; 89: 2266-73. Kondo K, Chijiiwa K, Nagano M, et al. Comparison of seven prognostic staging systems in patients who undergo hepatectomy for hepatocellular carcinoma. Hepatogastroenterology 2007; 54: 1534-8. Taefi A, Abrishami A, Nasseri-Moghaddam S, et al. Surgical resection versus liver transplant for patients with hepatocellular carcinoma. Cochrane Database Syst Rev 2013; 6: CD006935. Fan ST. Hepatocellular carcinoma —resection or transplant? Nat Rev Gastroenterol Hepatol 2012; 9: 732-7. Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012; 13: e11-22. European Association for the Study of the L, European Organisation for R, Treatment of C. EASL–EORTC Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-43. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693-9. Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl 2011; 17(Suppl. 2): S44-57. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19: 329-38. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698-711. Freeman RB, Jr., Wiesner RH, Harper A, et al. The new liver allocation system: moving toward evidence-based transplantation policy. Liver Transpl 2002; 8: 851-8. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001; 33: 1394-403. Otto G, Herber S, Heise M, et al. Response to transarterial chemoembolization as a biological selection criterion

s36

139.

140.

141.

142.

143.

144.

145. 146.

147.

148. 149. 150. 151.

152. 153. 154. 155.

156.


for liver transplantation in hepatocellular carcinoma. Liver Transpl 2006; 12: 1260-7. Gordon-Weeks AN, Snaith A, Petrinic T, et al. Systematic review of outcome of downstaging hepatocellular cancer before liver transplantation in patients outside the Milan criteria. Br J Surg 2011; 98: 1201-8. Yang SH, Suh KS, Lee HW, et al. A revised scoring system utilizing serum alphafetoprotein levels to expand candidates for living donor transplantation in hepatocellular carcinoma. Surgery 2007; 141: 598-609. Yao FY, Kerlan RK, Jr., Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008; 48: 819-27. Merani S, Majno P, Kneteman NM, et al. The impact of waiting list alpha-fetoprotein changes on the outcome of liver transplant for hepatocellular carcinoma. J Hepatol 2011; 55: 814-19. Lai Q, Avolio AW, Manzia TM, et al. Role of alpha-fetoprotein in selection of patients with hepatocellular carcinoma waiting for liver transplantation: must we reconsider it? Int J Biol Markers 2011; 26: 153-9. Xu X, Ke QH, Shao ZX, et al. The value of serum alpha-fetoprotein in predicting tumor recurrence after liver transplantation for hepatocellular carcinoma. Dig Dis Sci 2009; 54: 385-8. Jang JW, You CR, Kim CW, et al. Benefit of downsizing hepatocellular carcinoma in a liver transplant population. Aliment Pharmacol Ther 2010; 31: 415-23. Toso C, Asthana S, Bigam DL, et al. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the Scientific Registry of Transplant Recipients database. Hepatology 2009; 49: 832-8. Pomfret EA, Washburn K, Wald C, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 2010; 16: 262-78. Belghiti J, Panis Y, Farges O, et al. Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg 1991; 214: 114-17. Lang H, Sotiropoulos GC, Domland M, et al. Liver resection for hepatocellular carcinoma in non-cirrhotic liver without underlying viral hepatitis. Br J Surg 2005; 92: 198-202. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19: 329-38. Torzilli G, Makuuchi M, Inoue K, et al. No-mortality liver resection for hepatocellular carcinoma in cirrhotic and noncirrhotic patients: is there a way? A prospective analysis of our approach. Arch Surg 1999; 134: 984-92. Rees M, Plant G, Wells J, Bygrave S. One hundred and fifty hepatic resections: evolution of technique towards bloodless surgery. Br J Surg 1996; 83: 1526-9. Ikai I, Arii S, Okazaki M, et al. Report of the 17th nationwide follow-up survey of primary liver cancer in Japan. Hepatol Res 2007; 37: 676-91. Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol 2008; 48(Suppl. 1): S20-37. Roayaie S, Blume IN, Thung SN, et al. A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma. Gastroenterology 2009; 137: 850-5. Poon RT, Fan ST, Lo CM, et al. Extended hepatic resection for hepatocellular carcinoma in patients with cirrhosis: is it justified? Ann Surg 2002; 236: 602-11.

, 2014; 13 (Supl. 1): s4-s40

157. Mazzaferro V, Romito R, Schiavo M, et al. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology 2006; 44: 1543-54. 158. Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 2008; 134: 1908-16. 159. Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology 2000; 32: 1224-9. 160. Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356: 802-7. 161. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a western center. Ann Surg 1999; 229: 790-9; discussion 799-800. 162. Grazi GL, Ercolani G, Pierangeli F, et al. Improved results of liver resection for hepatocellular carcinoma on cirrhosis give the procedure added value. Ann Surg 2001; 234: 71-8. 163. Yamamoto M, Takasaki K, Ohtsubo T, et al. Effectiveness of systematized hepatectomy with Glisson’s pedicle transection at the hepatic hilus for small nodular hepatocellular carcinoma: retrospective analysis. Surgery 2001; 130: 443-8. 164. Nakashima Y, Nakashima O, Tanaka M, et al. Portal vein invasion and intrahepatic micrometastasis in small hepatocellular carcinoma by gross type. Hepatol Res 2003; 26: 142-7. 165. Poon RT, Fan ST, Ng IO, Wong J. Significance of resection margin in hepatectomy for hepatocellular carcinoma: a critical reappraisal. Ann Surg 2000; 231: 544-51. 166. Imamura H, Matsuyama Y, Miyagawa Y, et al. Prognostic significance of anatomical resection and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma. Br J Surg 1999; 86: 1032-8. 167. Hasegawa K, Kokudo N, Imamura H, et al. Prognostic impact of anatomic resection for hepatocellular carcinoma. Ann Surg 2005; 242: 252-9. 168. Kosuge T, Makuuchi M, Takayama T, et al. Long-term results after resection of hepatocellular carcinoma: experience of 480 cases. Hepatogastroenterology 1993; 40: 328-32. 169. Vauthey JN, Lauwers GY, Esnaola NF, et al. Simplified staging for hepatocellular carcinoma. J Clin Oncol 2002; 20: 1527-36. 170. Okada S, Shimada K, Yamamoto J, et al. Predictive factors for postoperative recurrence of hepatocellular carcinoma. Gastroenterology 1994; 106: 1618-24. 171. Shirabe K, Kanematsu T, Matsumata T, et al. Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: univariate and multivariate analyses. Hepatology 1991; 14: 802-5. 172. Adachi E, Maeda T, Matsumata T, et al. Risk factors for intrahepatic recurrence in human small hepatocellular carcinoma. Gastroenterology 1995; 108: 768-75. 173. Poon RT, Fan ST, Lo CM, et al. Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Ann Surg 1999; 229: 216-22. 174. Minagawa M, Makuuchi M, Takayama T, Kokudo N. Selection criteria for repeat hepatectomy in patients with


recurrent hepatocellular carcinoma. Ann Surg 2003; 238: 703-10. 175. Nagasue N, Uchida M, Makino Y, et al. Incidence and factors associated with intrahepatic recurrence following resection of hepatocellular carcinoma. Gastroenterology 1993; 105: 488-94. 176. Morimoto O, Nagano H, Sakon M, et al. Diagnosis of intrahepatic metastasis and multicentric carcinogenesis by microsatellite loss of heterozygosity in patients with multiple and recurrent hepatocellular carcinomas. J Hepatol 2003; 39: 215-21. 177. Miyake Y, Takaki A, Iwasaki Y, Yamamoto K. Meta-analysis: interferon-alpha prevents the recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma. J Viral Hepat 2010; 17: 287-92. 178. Yamasaki S, Hasegawa H, Kinoshita H, et al. A prospective randomized trial of the preventive effect of pre-operative transcatheter arterial embolization against recurrence of hepatocellular carcinoma. Jpn J Cancer Res 1996; 87: 206-11. 179. Kubo S, Nishiguchi S, Hirohashi K, et al. Randomized clinical trial of long-term outcome after resection of hepatitis C virus-related hepatocellular carcinoma by postoperative interferon therapy. Br J Surg 2002; 89: 418-22. 180. Breitenstein S, Dimitroulis D, Petrowsky H, et al. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg 2009; 96: 975-81. 181. Ikeda K, Arase Y, Saitoh S, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology 2000; 32: 228-32. 182. Schwartz JD, Schwartz M, Mandeli J, Sung M. Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol 2002; 3: 593-603. 183. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698-711. 184. Shen YC, Hsu C, Chen LT, et al. Adjuvant interferon therapy after curative therapy for hepatocellular carcinoma (HCC): a meta-regression approach. J Hepatol 2010; 52: 889-94. 185. Singal AG, Waljee AK, Shiffman M, et al. Meta-analysis: re-treatment of genotype I hepatitis C nonresponders and relapsers after failing interferon and ribavirin combination therapy. Aliment Pharmacol Ther 2010; 32: 969-83. 186. Lau WY, Leung TW, Ho SK, et al. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999; 353: 797-801. 187. Boucher E, Corbinais S, Rolland Y, et al. Adjuvant intraarterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma. Hepatology 2003; 38: 1237-41. 188. Muto Y, Moriwaki H, Ninomiya M, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 1996; 334: 1561-7. 189. Yoshida H, Shiratori Y, Kudo M, et al. Effect of vitamin K2 on the recurrence of hepatocellular carcinoma. Hepatology 2011; 54: 532-40.

, 2014; 13 (Supl. 1): s4-s40

s37

190. Samuel M, Chow PK, Chan Shih-Yen E, et al. Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma. Cochrane Database Syst Rev 2009; CD001199. 191. Sato S, Shiratori Y, Imamura M, et al. Power Doppler signals after percutaneous ethanol injection therapy for hepatocellular carcinoma predict local recurrence of tumors: a prospective study using 199 consecutive patients. J Hepatol 2001; 35: 225-34. 192. Lencioni R, Crocetti L. Local-regional treatment of hepatocellular carcinoma. Radiology 2012; 262: 43-58. 193. Lencioni R, Bartolozzi C, Caramella D, et al. Treatment of small hepatocellular carcinoma with percutaneous ethanol injection. Analysis of prognostic factors in 105 western patients. Cancer 1995; 76: 1737-46. 194. Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995; 197: 101-8. 195. Khan KN, Yatsuhashi H, Yamasaki K et al. Prospective analysis of risk factors for early intrahepatic recurrence of hepatocellular carcinoma following ethanol injection. J Hepatol 2000; 32: 269-78. 196. Huo TI, Huang YH, Wu JC, et al. Comparison of percutaneous acetic acid injection and percutaneous ethanol injection for hepatocellular carcinoma in cirrhotic patients: a prospective study. Scand J Gastroenterol 2003; 38: 770-8. 197. Cho YK, Kim JK, Kim MY, et al. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology 2009; 49: 453-9. 198. N’Kontchou G, Mahamoudi A, Aout M, et al. Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 western patients with cirrhosis. Hepatology 2009; 50: 1475-83. 199. Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 2008; 47: 82-9. 200. Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006; 243: 321-8. 201. Lu DS, Yu NC, Raman SS, et al. Radiofrequency ablation of hepatocellular carcinoma: treatment success as defined by histologic examination of the explanted liver. Radiology 2005; 234: 954-60. 202. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 429-42. 203. Chen BB, Shih IL, Wu CH, et al. Comparison of characteristics and transarterial chemoembolization outcomes in patients with unresectable hepatocellular carcinoma and different viral etiologies. J Vasc Interv Radiol 2014; 25: 371-8. 204. Chern MC, Chuang VP, Liang CT, et al. Transcatheter arterial chemoembolization for advanced hepatocellular carcinoma with portal vein invasion: safety, efficacy, and prognostic factors. J Vasc Interv Radiol 2014; 25: 32-40. 205. Xie F, Zang J, Guo X, et al. Comparison of transcatheter arterial chemoembolization and microsphere embolization for treatment of unresectable hepatocellular carci-

s38


noma: a meta-analysis. J Cancer Res Clin Oncol 2012; 138: 455-62. 206. Huang K, Zhou Q, Wang R, et al. Doxorubicin-eluting bead versus conventional transarterial chemoembolization for the treatment of HCC: a meta-analysis. J Gastroenterol Hepatol J 2013 Nov 13. doi: 10.1111/jgh.12439. 207. Shi HY, Wang SN, Wang SC, et al. Preoperative transarterial chemoembolization and resection for hepatocellular carcinoma: a nationwide Taiwan database analysis of long-term outcome predictors. J Surg Oncol 2014; 109: 487-93. 208. Zhou Y, Zhang X, Wu L, et al. Meta-analysis: preoperative transcatheter arterial chemoembolization does not improve prognosis of patients with resectable hepatocellular carcinoma. BMC Gastroenterol 2013; 13: 51. 209. Gu L, Liu H, Fan L, et al. Treatment outcomes of transcatheter arterial chemoembolization combined with local ablative therapy versus monotherapy in hepatocellular carcinoma: a meta-analysis. J Cancer Res Clin Oncol 2014; 140: 199-210. 210. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42: 1208-36. 211. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35: 421-30. 212. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-90. 213. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10: 25-34. 214. Hollebecque A, Cattan S, Romano O, et al. Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score. Aliment Pharmacol Ther 2011; 34: 1193-201. 215. Kim JE, Ryoo BY, Ryu MH, et al. Sorafenib for hepatocellular carcinoma according to Child-Pugh class of liver function. Cancer Chemother Pharmacol 2011; 68: 1285-90. 216. Ozenne V, Paradis V, Pernot S, et al. Tolerance and outcome of patients with unresectable hepatocellular carcinoma treated with sorafenib. Eur J Gastroenterol Hepatol 2010; 22: 1106-10. 217. Pressiani T, Boni C, Rimassa L, et al. Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis. Ann Oncol 2013; 24: 406-11. 218. Villanueva A, Llovet JM. Second-line therapies in hepatocellular carcinoma: emergence of resistance to sorafenib. Clin Cancer Res 2012; 18: 1824-6. 219. Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 2013; 14: 55-63. 220. Llovet JM, Decaens T, Raoul JL, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 2013; 31: 3509-16. 221. Yau T, Wong H, Chan P, et al. Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease. Invest New Drugs 2012; 30: 2384-90.

, 2014; 13 (Supl. 1): s4-s40

222. Finn RS, Poon RT, Yau T, et al. Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma. J Hepatol 2013; 59: 1271-7. 223. Dufour JF, Hoppe H, Heim MH, et al. Continuous administration of sorafenib in combination with transarterial chemoembolization in patients with hepatocellular carcinoma: results of a phase I study. Oncologist 2010; 15: 1198-204. 224. Chung YH, Han G, Yoon JH, et al. Interim analysis of START: Study in Asia of the combination of TACE (transcatheter arterial chemoembolization) with sorafenib in patients with hepatocellular carcinoma trial. Int J Cancer 2013; 132: 2448-58. 225. Wang SN, Chuang SC, Lee KT. Efficacy of sorafenib as adjuvant therapy to prevent early recurrence of hepatocellular carcinoma after curative surgery: a pilot study. Hepatol Res 2013 May 14. doi: 10.1111/hepr.12159. 226. Qu XD, Chen CS, Wang JH, et al. The efficacy of TACE combined sorafenib in advanced stages hepatocellullar carcinoma. BMC Cancer 2012; 12: 263. 227. Petrini I, Lencioni M, Ricasoli M, et al. Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2012; 69: 773-80. 228. Gish RG, Porta C, Lazar L, et al. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol 2007; 25: 3069-75. 229. Yeo W, Mok TS, Zee B, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005; 97: 1532-8. 230. Lai CL, Lau JY, Wu PC, et al. Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. Hepatology 1993; 17: 389-94. 231. Garcia-Leiva J, Gamboa-Dominguez A, Ceron-Lizarraga T, et al. Response of negative estrogen-receptor hepatocarcinoma to tamoxifen, and survival of non-resectable patients. Ann Hepatol 2006; 5: 263-7. 232. Nowak AK, Stockler MR, Chow PK, Findlay M. Use of tamoxifen in advanced-stage hepatocellular carcinoma. A systematic review. Cancer 2005; 103: 1408-14. 233. Nowak A, Findlay M, Culjak G, Stockler M. Tamoxifen for hepatocellular carcinoma. Cochrane Database Syst Rev 2004; CD001024. 234. Wang Z, Wu XL, Zeng WZ, et al. Meta-analysis of the efficacy of sorafenib for hepatocellular carcinoma. Asian Pac J Cancer Prev 2013; 14: 691-4. 235. McEvoy LK, Cope DG, Oncology Nursing Society. Caring for the older adult with cancer in the ambulatory setting. Pittsburgh, Pa.: Oncology Nursing Society 2012. 236. El-Serag HB, Siegel AB, Davila JA, Shaib YH, Cayton-Woody M, McBride R, et al. Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the United States: a population-based study. J Hepatol 2006, 44(1): 158-66. 237. Ahmedzai S. The rational use of opioid analgesics for cancer pain with a critique of the WHO 3-step ladder. In: Cancer pain management: advancing towards optimal symptom management. London: Henry Stewart Talks 2009: 1 streaming video file (58 min.). 238. Kotb HI, El-Kady SA, Emara SE, Fouad EA, El-Kabsh MY. Pharmacokinetics of controlled release morphine (MST) in patients with liver carcinoma. Br J Anaesth 2005; 94(1): 95-9.


239. Huang TW, Lin CC. The mediating effects of depression on sleep disturbance and fatigue: symptom clusters in patients with hepatocellular carcinoma. Cancer Nurs 2009; 32(5): 398-403. 240. Chow PK, Machin D, Chen Y, Zhang X, Win KM, Hoang HH, et al. Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma. Br J Cancer 2011; 105(7): 945-52. 241. Cappa FM, Cantarini MC, Magini G, Zambruni A, Bendini C, Santi V, et al. Effects of the combined treatment with thalidomide, megestrol and interleukine-2 in cirrhotic patients with advanced hepatocellular carcinoma. A pilot study. Dig Liver Dis 2005; 37(4): 254-9. 242. Sohara N, Takagi H, Abe T, Hashimoto Y, Kojima A, Takahashi H, et al. Nausea and vomiting induced by arterial chemo-embolization in patients with hepatocellular carcinoma and the antiemetic effect of ondansetron hydrochloride. Support Care Cancer 1999; 7(2): 84-8. 243. Martin JA, Slivka A, Rabinovitz M, Carr BI, Wilson J, Silverman WB. ERCP and stent therapy for progressive jaundice in hepatocellular carcinoma: which patients benefit, which patients don’t? Dig Dis Sci 1999; 44(7): 1298-302. 244. Haas M, Moore-Higgs GJ, Oncology Nursing Society. Principles of skin care and the oncology patient. Pittsburgh: Oncology Nursing Society; 2010. 245. Orloff MJ, Isenberg JI, Wheeler HO, Haynes KS, JinichBrook H, Rapier R, et al. A randomized controlled trial of emergency treatment of bleeding esophageal varices in cirrhosis for hepatocellular carcinoma. Am J Surg 2012; 203(2): 182-90. 246. Lang BH, Poon RT, Fan ST, Wong J. Outcomes of patients with hepatocellular carcinoma presenting with variceal bleeding. Am J Gastroenterol 2004; 99(11): 2158-65. 247. Lo GH, Lai KH, Chang CF, Shen MT, Jeng JS, Huang RL, et al. Endoscopic injection sclerotherapy vs. endoscopic variceal ligation in arresting acute variceal bleeding for patients with advanced hepatocellular carcinoma. J Hepatol 1994; 21(6): 1048-52. 248. Iwakiri R, Koyama T, Hirano M, Uchida Y, Ishibashi S, Kuwahara A, et al. Endoscopic injection sclerotherapy for esophageal varices prolonged survival of patients with hepatocellular carcinoma complicating liver cirrhosis. Gastrointest Endosc 2000; 51(5): 569-72. 249. Chen WC, Hou MC, Lin HC, Lee FY, Yeh YY, Chang FY, et al. Feasibility and potential benefit of maintenance endoscopic variceal ligation in patients with unresectable hepatocellular carcinoma and acute esophageal variceal hemorrhage: a controlled trial. Gastrointest Endosc 2001; 54(1): 18-23. 250. Jiang ZB, Shan H, Shen XY, Huang MS, Li ZR, Zhu KS, et al. Transjugular intrahepatic portosystemic shunt for palliative treatment of portal hypertension secondary to portal vein tumor thrombosis. World J Gastroenterol 2004; 10(13): 1881-4. 251. Hawkins MA, Dawson LA. Radiation therapy for hepatocellular carcinoma: from palliation to cure. Cancer 2006; 106(8): 1653-63. 252. Shun SC, Chiou JF, Lai YH, Yu PJ, Wei LL, Tsai JT, et al. Changes in quality of life and its related factors in liver cancer patients receiving stereotactic radiation therapy. Sup Care Cancer 2008; 16(9): 1059-65. 253. Van Cleave J, Devine P, Odom-Ball P. Multidisciplinary care of hepatocellular carcinoma. Cancer Pract 1999; 7(6): 302-8.

, 2014; 13 (Supl. 1): s4-s40

s39

254. Evert M, Dombrowski F. Hepatocellular carcinoma in the non-cirrhotic liver. Pathologe 2008; 29: 47-52. 255. Trevisani F, Frigerio M, Santi V, et al. Hepatocellular carcinoma in non-cirrhotic liver: a reappraisal. Dig Liver Dis 2010; 42: 341-7. 256. Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis 2005; 25: 143-54. 257. Okuda K, Nakashima T, Kojiro M, et al. Hepatocellular carcinoma without cirrhosis in Japanese patients. Gastroenterology 1989; 97: 140-6. 258. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009; 27: 1485-91. 259. Borie F, Bouvier AM, Herrero A, et al. Treatment and prognosis of hepatocellular carcinoma: a population based study in France. J Surg Oncol 2008; 98: 505-9. 260. Calvet X, Bruix J, Bru C, et al. Natural history of hepatocellular carcinoma in Spain. Five year’s experience in 249 cases. J Hepatol 1990; 10: 311-17. 261. Stoot JH, Coelen RJ, De Jong MC, Dejong CH. Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases. HPB (Oxford) 2010; 12: 509-22. 262. Nzeako UC, Goodman ZD, Ishak KG. Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients. Am J Clin Pathol 1996; 105: 65-75. 263. Turati F, Edefonti V, Talamini R, et al. Family history of liver cancer and hepatocellular carcinoma. Hepatology 2012; 55: 1416-25. 264. Loomba R, Liu J, Yang HI, et al. Synergistic effects of family history of hepatocellular carcinoma and hepatitis B virus infection on risk for incident hepatocellular carcinoma. Clin Gastroenterol Hepatol 2013; 11: 1636-45; e1631-1633. 265. Albeldawi M, Soliman M, Lopez R, Zein NN. Hepatitis C virus-associated primary hepatocellular carcinoma in noncirrhotic patients. Dig Dis Sci 2012; 57: 3265-70. 266. Lok AS, Seeff LB, Morgan TR, et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 2009; 136: 138-48. 267. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020-2. 268. Guzman G, Brunt EM, Petrovic LM, et al. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Med 2008; 132: 1761-6. 269. Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 2012; 56: 1384-91. 270. Yasui K, Hashimoto E, Komorizono Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011; 9: 428-33; quiz e450. 271. Lerut J, Mergental H, Kahn D, et al. Place of liver transplantation in the treatment of hepatocellular carcinoma in the normal liver. Liver Transpl 2011; 17(Suppl. 2): S90-7. 272. Decaens T, Laurent A, Luciani A. Liver transplantation for hepatocellular carcinoma in non-cirrhotic livers regardless of the number and size of tumours? J Hepatol 2012; 57: 235-6. 273. Mergental H, Adam R, Ericzon BG, et al. Liver transplantation for unresectable hepatocellular carcinoma in normal livers. J Hepatol 2012; 57: 297-305.

s40


274. Houben KW, McCall JL. Liver transplantation for hepatocellular carcinoma in patients without underlying liver disease: a systematic review. Liver Transpl Surg 1999; 5: 91-5. 275. Allan BJ, Wang B, Davis JS, et al. A review of 218 pediatric cases of hepatocellular carcinoma. J Pediatr Surg 2014; 49: 166-71. 276. McAteer JP, Goldin AB, Healey PJ, Gow KW. Surgical treatment of primary liver tumors in children: outcomes analysis of resection and transplantation in the SEER database. Pediatr Transplant 2013; 17: 744-50. 277. McAteer JP, Goldin AB, Healey PJ, Gow KW. Hepatocellular carcinoma in children: epidemiology and the impact of regional lymphadenectomy on surgical outcomes. J Pediatr Surg 2013; 48: 2194-201. 278. Beaunoyer M, Vanatta JM, Ogihara M, et al. Outcomes of transplantation in children with primary hepatic malignancy. Pediatr Transplant 2007; 11: 655-60. 279. Ismail H, Broniszczak D, Kalicinski P, et al. Liver transplantation in children with hepatocellular carcinoma. Do Milan criteria apply to pediatric patients? Pediatr Transplant 2009; 13: 682-92. 280. Czauderna P, Mackinlay G, Perilongo G, et al. Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 2002; 20: 2798-804. 281. Weeda VB, Murawski M, McCabe AJ, et al. Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma —results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. Eur J Cancer 2013; 49: 2698-704. 282. Villanueva A, Llovet JM. Second-line therapies in hepatocellular carcinoma: emergence of resistance to sorafenib. Clin Cancer Res 2012; 18: 1824-6. 283. Zhang X, Yang XR, Huang XW, et al. Sorafenib in treatment of patients with advanced hepatocellular carcino-

, 2014; 13 (Supl. 1): s4-s40

ma: a systematic review. Hepatobil Pancreat Dis Int 2012; 11: 458-66. 284. Glade Bender J, Blaney SM, Borinstein S, et al. A phase I trial and pharmacokinetic study of aflibercept (VEGF Trap) in children with refractory solid tumors: a children’s oncology group phase I consortium report. Clin Cancer Res 2012; 18: 5081-9. 285. Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012; 57: 821-9. 286. Personeni N, Bozzarelli S, Pressiani T, et al. Usefulness of alpha-fetoprotein response in patients treated with sorafenib for advanced hepatocellular carcinoma. J Hepatol 2012; 57: 101-7. 287. Kane RC, Farrell AT, Madabushi R, et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist 2009; 14: 95-100. 288. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-90. 289. Schmid I, Haberle B, Albert MH, et al. Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. Pediatr Blood Cancer 2012; 58: 539-44. 290. Hertl M, Cosimi AB. Liver transplantation for malignancy. Oncologist 2005; 10: 269-81. 2 9 1 . Czauderna P, Zbrzezniak G, Narozanski W, et al. Preliminary experience with arterial chemoembolization for hepatoblastoma and hepatocellular carcinoma in children. Pediatr Blood Cancer 2006; 46: 825-8. 292. Malogolowkin MH, Stanley P, Steele DA, Ortega JA. Feasibility and toxicity of chemoembolization for children with liver tumors. J Clin Oncol 2000; 18: 1279-84. 293. Arcement CM, Towbin RB, Meza MP, et al. Intrahepatic chemoembolization in unresectable pediatric liver malignancies. Pediatr Radiol 2000; 30: 779-85.